Search

Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and they may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that a 2-weeks exposure to dim light at night (DLaN) disrupts diurnal rhythms, increases repetitive behaviors and reduces social interactions in contactin-associated protein-like 2 knock out (Cntnap2 KO) mice. The deleterious effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480 nm). In this study, the usage of a light-emitting diode array enabled us to shift the spectral properties of the DLaN while keeping the intensity of the illumination at 10 lx. First, we confirmed that the short-wavelength enriched lighting produced strong acute suppression of locomotor activity (masking), robust light-induced phase shifts, and cFos expression in the suprachiasmatic nucleus in wild-type (WT) mice, while the long-wavelength enriched lighting evoked much weaker responses. Opn4DTA mice, lacking the melanopsin expressing ipRGCs, were resistant to DLaN effects. Importantly, shifting the DLaN stimulus to longer wavelengths mitigated the negative impact on the activity rhythms and autistic behaviors (i.e. reciprocal social interactions, repetitive grooming) in the Cntnap2 KO as well as in WT mice. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in in the basolateral amygdala (BLA) as well as in the peri-habenula region raising that possibility that these cell populations may mediate the effects. Broadly, our findings are consistent with the recommendation that spectral properties of light at night should be considered to optimize health in neurotypical as well as vulnerable populations.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

INTRODUCTION: Traumatic brain injury (TBI) is one of the highest public health priorities, especially among military personnel where comorbidity with post-traumatic stress symptoms and resulting consequences is high. Brain injury and post-traumatic stress symptoms are both characterized by dysfunctional brain networks, with the amygdala specifically implicated as a region with both structural and functional abnormalities. METHODS: This study examined the structural volumetrics and resting state functional connectivity of 68 Active Duty Service Members with or without chronic mild TBI (mTBI) and comorbid symptoms of Post-Traumatic Stress (PTS). RESULTS AND DISCUSSION: Structural analysis of the amygdala revealed no significant differences in volume between mTBI and healthy comparison participants with and without post-traumatic stress symptoms. Resting state functional connectivity with bilateral amygdala revealed decreased anterior network connectivity and increased posterior network connectivity in the mTBI group compared to the healthy comparison group. Within the mTBI group, there were significant regions of correlation with amygdala that were modulated by PTS severity, including networks implicated in emotional processing and executive functioning. An examination of a priori regions of amygdala connectivity in the default mode network, task positive network, and subcortical structures showed interacting influences of TBI and PTS, only between right amygdala and right putamen. These results suggest that mTBI and PTS are associated with hypo-frontal and hyper-posterior amygdala connectivity. Additionally, comorbidity of these conditions appears to compound these neural activity patterns. PTS in mTBI may change neural resource recruitment for information processing between the amygdala and other brain regions and networks, not only during emotional processing, but also at rest.

BackgroundLow intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively.Objective/hypothesisWe sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region.MethodsIn this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC).ResultstFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity.ConclusionWe demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

Anxious traits are elevated in eating disorders (EDs), are considered risk factors for ED development, and trait anxiety has been linked to ED psychopathology. How trait anxiety relates to ED neurobiology is not well understood. In this study 197 individuals across the ED spectrum (anorexia nervosa n = 91; other specified EDs n = 34; bulimia nervosa n = 56; binge ED n = 16), and 120 healthy controls were assessed for anxious traits and learned to expect and receive caloric or neutral taste stimuli during brain imaging. Amygdala sucrose expectation response differed across groups (Wilk's lambda = 0.945, p = 0.023), and was higher on the left in anorexia nervosa compared to healthy controls (p = 0.002). Expected sucrose receipt response across taste reward regions was not different between groups. In the ED sample, trait anxiety negatively moderated the relationship between amygdala expectation and right dorsal (p = 0.0062) and ventral (p = 0.0046) anterior insula receipt response. A subgroup analysis showed similar results for anorexia nervosa, and partially in bulimia nervosa. Across EDs, appetitive motivation correlated positively with bilateral orbitofrontal cortex, caudate head, and ventral striatal sucrose receipt response (r = 0.215 to 0.179, p = 0.002 to 0.012). Across the study sample, trait anxiety showed an inverted-U-shaped relationship with right (r = 0.147, p = 0.034) and left (r = 0.162, p = 0.016) amygdala expectation response. Amygdala sucrose expectation response is elevated in anorexia nervosa, correlates with sucrose receipt response, and this relationship is negatively moderated by trait anxiety across EDs. Trait anxiety may have an important role in how expectation drives taste stimulus receipt brain response and perhaps food approach in individuals with EDs.

The amygdala plays a role in emotion, learning, and memory and has been implicated in behavioral disorders. Better understanding of the amygdala circuitry is crucial to develop new therapies for these disorders. We used data from 200 healthy-subjects from the human connectome project. Using probabilistic tractography, we created population statistical maps of amygdala connectivity to brain regions involved in limbic, associative, memory, and reward circuits. Based on the amygdala connectivity with these regions, we applied k-means clustering to parcellate the amygdala into three clusters. The resultant clusters were averaged across all subjects and the main white-matter pathways of the amygdala from each averaged cluster were generated. Amygdala parcellation into three clusters showed a medial-to-lateral pattern. The medial cluster corresponded with the centromedial and cortical nuclei, the basal cluster with the basal nuclei and the lateral cluster with the lateral nuclei. The connectivity analysis revealed different white-matter pathways consistent with the anatomy of the amygdala circuit. This in vivo connectivity-based parcellation of the amygdala delineates three clusters of the amygdala in a mediolateral pattern based on its connectivity with brain areas involved in cognition, memory, emotion, and reward. The human amygdala circuit presented in this work provides the first step for personalized amygdala circuit mapping for patients with behavioral disorders.

A central question in consciousness theories is whether one is dealing with a dichotomous ("all-or-none") or a gradual phenomenon. In this 7T fMRI study, we investigated whether dichotomy or gradualness in fact depends on the brain region associated with perceptual awareness reports. Both male and female human subjects performed an emotion discrimination task (fear vs neutral bodies) presented under continuous flash suppression with trial-based perceptual awareness measures. Behaviorally, recognition sensitivity increased linearly with increased stimuli awareness and was at chance level during perceptual unawareness. Physiologically, threat stimuli triggered a slower heart rate than neutral ones during "almost clear" stimulus experience, indicating freezing behavior. Brain results showed that activity in the occipitotemporal, parietal, and frontal regions as well as in the amygdala increased with increased stimulus awareness while early visual areas showed the opposite pattern. The relationship between temporal area activity and perceptual awareness best fitted a gradual model while the activity in frontoparietal areas fitted a dichotomous model. Furthermore, our findings illustrate that specific experimental decisions, such as stimulus type or the approach used to evaluate awareness, play pivotal roles in consciousness studies and warrant careful consideration. [ABSTRACT FROM AUTHOR]

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Credependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP [ABSTRACT FROM AUTHOR]

The Slitrk family consists of six synaptic adhesion molecules, some of which are associated with neuropsychiatric disorders. In this study, we aimed to investigate the physiological role of Slitrk4 by analyzing Slitrk4 knockout (KO) mice. The Slitrk4 protein was widely detected in the brain and was abundant in the olfactory bulb and amygdala. In a systematic behavioral analysis, male Slitrk4 KO mice exhibited an enhanced fear memory acquisition in a cued test for classical fear conditioning, and social behavior deficits in reciprocal social interaction tests. In an electrophysiological analysis using amygdala slices, Slitrk4 KO mice showed enhanced long-term potentiation in the thalamo-amygdala afferents and reduced feedback inhibition. In the molecular marker analysis of Slitrk4 KO brains, the number of calretinin (CR)-positive interneurons was decreased in the anterior part of the lateral amygdala nuclei at the adult stage. In in vitro experiments for neuronal differentiation, Slitrk4-deficient embryonic stem cells were defective in inducing GABAergic interneurons with an altered response to sonic hedgehog signaling activation that was involved in the generation of GABAergic interneuron subsets. These results indicate that Slitrk4 function is related to the development of inhibitory neurons in the fear memory circuit and would contribute to a better understanding of osttraumatic stress disorder, in which an altered expression of Slitrk4 has been reported. [ABSTRACT FROM AUTHOR]

Background and Aims Increasing data suggest that stress-related neural activity (SNA) is associated with subsequent major adverse cardiovascular events (MACE) and may represent a therapeutic target. Current evidence is exclusively based on populations from the U.S. and Asia where limited information about cardiovascular disease risk was available. This study sought to investigate whether SNA imaging has clinical value in a well-characterized cohort of cardiovascular patients in Europe. Methods In this single-centre study, a total of 963 patients (mean age 58.4 ± 16.1 years, 40.7% female) with known cardiovascular status, ranging from 'at-risk' to manifest disease, and without active cancer underwent 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography between 1 January 2005 and 31 August 2019. Stress-related neural activity was assessed with validated methods and relations between SNA and MACE (non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, and cardiovascular death) or all-cause mortality by time-to-event analysis. Results Over a maximum follow-up of 17 years, 118 individuals (12.3%) experienced MACE, and 270 (28.0%) died. In univariate analyses, SNA significantly correlated with an increased risk of MACE (sub-distribution hazard ratio 1.52, 95% CI 1.05–2.19; P =.026) or death (hazard ratio 2.49, 95% CI 1.96–3.17; P <.001). In multivariable analyses, the association between SNA imaging and MACE was lost when details of the cardiovascular status were added to the models. Conversely, the relationship between SNA imaging and all-cause mortality persisted after multivariable adjustments. Conclusions In a European patient cohort where cardiovascular status is known, SNA imaging is a robust and independent predictor of all-cause mortality, but its prognostic value for MACE is less evident. Further studies should define specific patient populations that might profit from SNA imaging. [ABSTRACT FROM AUTHOR]

Information storage in the brain involves different memory types and stages that are processed by several brain regions. Cholinergic pathways through acetylcholine receptors actively participate on memory modulation, and their disfunction is associated with cognitive decline in several neurological disorders. During the last decade, the role of α7 subtype of nicotinic acetylcholine receptors in different memory stages has been studied. However, the information about their role in memory processing is still scarce. In this review, we attempt to identify brain areas where α7 nicotinic receptors have an essential role in different memory types and stages. In addition, we discuss recent work implicating—or not—α7 nicotinic receptors as promising pharmacological targets for memory impairment associated with neurological disorders. [ABSTRACT FROM AUTHOR]

Alterations in the extracellular matrix are common in patients with epilepsy and animal models of epilepsy, yet whether they are the cause or consequence of seizures and epilepsy development is unknown. Using Theiler's murine encephalomyelitis virus (TMEV) infection-induced model of acquired epilepsy, we found de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major extracellular matrix component, in dentate gyrus (DG) and amygdala exclusively in mice with acute seizures. Preventing the synthesis of CSPGs specifically in DG and amygdala by deletion of the major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells revealed enhanced intrinsic and synaptic excitability in seizing mice that was significantly ameliorated by aggrecan deletion. In situ experiments suggested that dentate granule cell hyperexcitability results from negatively charged CSPGs increasing stationary cations on the membrane, thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. These results show increased expression of CSPGs in the DG and amygdala as one of the causal factors for TMEV-induced acute seizures. We also show identical changes in CSPGs in pilocarpine-induced epilepsy, suggesting that enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and potential therapeutic target. [ABSTRACT FROM AUTHOR]

Amygdala atrophy has been found in frontotemporal dementia (FTD), yet the specific changes of its subregions across different FTD phenotypes remain unclear. The aim of this study was to investigate the volumetric alterations of the amygdala subregions in FTD phenotypes and how they evolve with disease progression. Patients clinically diagnosed with behavioral variant FTD (bvFTD) (n = 20), semantic dementia (SD) (n = 20), primary nonfluent aphasia (PNFA) (n = 20), Alzheimer's disease (AD) (n = 20), and 20 matched healthy controls underwent whole brain structural MRI. The patient groups were followed up annually for up to 3.5 years. Amygdala nuclei were segmented using FreeSurfer, corrected by total intracranial volumes, and grouped into the basolateral, superficial, and centromedial subregions. Linear mixed effects models were applied to identify changes in amygdala subregional volumes over time. At baseline, bvFTD, SD, and AD displayed global amygdala volume reduction, whereas amygdala volume appeared to be preserved in PNFA. Asymmetrical amygdala atrophy (left > right) was most pronounced in SD. Longitudinally, SD and PNFA showed greater rates of annual decline in the right basolateral and superficial subregions compared to bvFTD and AD. The findings provide comprehensive insights into the differential impact of FTD pathology on amygdala subregions, revealing distinct atrophy patterns that evolve over disease progression. The characterization of amygdala subregional involvement in FTD and their potential role as biomarkers carry substantial clinical implications. [ABSTRACT FROM AUTHOR]

The amygdala might support an attentional bias for emotional faces. However, whether and how selective attention toward a specific valence modulates this bias is not fully understood. Likewise, it is unclear whether amygdala and cortical signals respond to emotion and attention in a similar way. We recorded gamma‐band activity (GBA, > 30 Hz) intracranially in the amygdalae of 11 patients with epilepsy and collected scalp recordings from 19 healthy participants. We presented angry, neutral, and happy faces randomly, and we denoted one valence as the target. Participants detected happy targets most quickly and accurately. In the amygdala, during attention to negative faces, low gamma‐band activity (LGBA, < 90 Hz) increased for angry compared with happy faces from 160 ms. From 220 ms onward, amygdala high gamma‐band activity (HGBA, > 90 Hz) was higher for angry and neutral faces than for happy ones. Monitoring neutral faces increased amygdala HGBA for emotions compared with neutral faces from 40 ms. Expressions were not differentiated in GBA while monitoring positive faces. On the scalp, only threat monitoring resulted in expression differentiation. Here, posterior LGBA was increased selectively for angry targets from 60 ms. The data show that GBA differentiation of emotional expressions is modulated by attention to valence: Top‐down‐controlled threat vigilance coordinates widespread GBA in favor of angry faces. Stimulus‐driven emotion differentiation in amygdala GBA occurs during a neutral attentional focus. These findings align with a multi‐pathway model of emotion processing and specify the role of GBA in this process. Our research challenges the idea of inherent automatic processing of emotional expressions in the amygdala. Instead, the differentiation of facial expressions in gamma‐band activity is modulated by valence monitoring. Threat monitoring facilitates top‐down, not bottom‐up, guidance of widespread gamma oscillations. Automatic attentional shifts toward emotion in the amygdala appear to occur only during a neutral focus. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) and stress influence overlapping neural circuits in the brain. The literature is mixed regarding the presence of sex differences in the neural response to acute stressors, and this issue has not been examined in individuals with AUD. We validated a stress functional magnetic resonance imaging (fMRI) paradigm in individuals with AUD and tested for sex differences. Methods: Twenty‐five treatment‐seeking individuals with AUD (15M/10F) were recruited to participate in the neuroimaging study linked to a clinical trial of ibudilast (NCT03594435). To assess social‐evaluative stress, participants completed the Montreal Imaging Stress Task (MIST). Whole brain and amygdala region‐of‐interest analyses were conducted. Subjective ratings of anxiety and distress were collected. Repeated measures ANCOVAs were performed to evaluate the effect of stress on anxiety and distress and to evaluate sex differences. Results: There were trend‐level effects of stress on anxiety ratings and amygdala activation (p's = 0.06). There was a significant effect of stress in the bilateral thalamus, ventral tegmental area, and paracingulate (Z's > 4.09, p's < 0.03). There was a trend‐level effect of sex on subjective ratings of stress (p's = 0.07). Females had higher amygdala activation in response to stress (p = 0.02). Females also had greater activation than males in the precuneus, posterior cingulate cortex, and right inferior frontal gyrus during acute stress (Z's > 3.56, p's < 0.03). Conclusions: This study provides an initial validation of the MIST in a sample of individuals with AUD. It also provides preliminary evidence of sex differences in the response to social‐evaluative stress, which is important, given the relevance of stress and negative emotionality as motivators for alcohol use in females. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic pain remains a major clinical problem that needs effective therapeutic agents. Glutamate delta 1 (GluD1) receptors and the protein cerebellin 1 (Cbln1) are down‐regulated in the central amygdala (CeA) in models of inflammatory and neuropathic pain. One treatment with Cbln1, intracerebroventricularly (ICV) or in CeA, normalized GluD1 and reduced AMPA receptor expression, resulting in lasting (7–10 days) pain relief. Unlike many CNS‐targeting biological agents, the structure of Cbln1 suggests potential blood–brain barrier penetration. Here, we have tested whether systemic administration of Cbln1 provides analgesic effects via action in the CNS. Experimental Approach: Analgesic effects of intravenous recombinant Cbln1 was assessed in complete Freund's adjuvant inflammatory pain model in mice. GluD1 knockout and a mutant form of Cbln1 were used. Key Results: A single intravenous injection of Cbln1 mitigated nocifensive and averse behaviour in both inflammatory and neuropathic pain models. This effect of Cbln1 was dependent on GluD1 receptors and required binding to the amino terminal domain of GluD1. Time course of analgesic effect was similar to previously reported ICV and intra‐CeA injection. GluD1 in both spinal cord and CeA was down –regulated in the inflammatory pain model, whereas GluD1 expression in spinal cord but not in CeA, was partly normalized by intravenous Cbln1. Importantly, recombinant Cbln1 was detected in the synaptoneurosomes in spinal cord but not in the CeA. Conclusions and Implications: Our results describe a novel mechanism by which systemic Cbln1 induces analgesia potentially by central actions involving normalization of signalling by spinal cord GluD1 receptors. [ABSTRACT FROM AUTHOR]

Prolonged or repeated exposure to stress elevates the risk of various psychological diseases, many of which are characterized by central nervous system dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are highly abundant in the mammalian brain. Although their precise expression and function remain unknown, they have been hypothesized to regulate transcriptional and post-transcriptional gene expression. In this investigation, we comprehensively analyzed whether restraint stress for 2 days altered the circRNA expression profile in the amygdala of male rats. The impact of restraint stress on behavior was evaluated using an elevated plus maze and open field test. Serum corticosterone levels were measured using an enzymelinked immunosorbent assay. A total of 10,670 circRNAs were identified using RNA sequencing. Ten circRNAs were validated by reverse transcription and quantitative polymerase chain reaction analysis. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyzes supported the notion that genes associated with differentially expressed circRNAs are primarily implicated in neuronal activity and neurotransmitter transport. Moreover, the three differentially expressed circRNAs showed high specificity in the amygdala. Overall, these findings indicate that differentially expressed circRNAs are highly enriched in the amygdala and offer a potential direction for further research on restraint stress. [ABSTRACT FROM AUTHOR]

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory. [ABSTRACT FROM AUTHOR]

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-- value and stimulus--stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning. [ABSTRACT FROM AUTHOR]

The human medial temporal lobe (MTL) plays a crucial role in recognizing visual objects, a key cognitive function that relies on the formation of semantic representations. Nonetheless, it remains unknown how visual information of general objects is translated into semantic representations in the MTL. Furthermore, the debate about whether the human MTL is involved in perception has endured for a long time. To address these questions, we investigated three distinct models of neural object coding--semantic coding, axisbased feature coding, and region-based feature coding--in each subregion of the human MTL, using high-resolution fMRI in two male and six female participants. Our findings revealed the presence of semantic coding throughout the MTL, with a higher prevalence observed in the parahippocampal cortex (PHC) and perirhinal cortex (PRC), while axis coding and region coding were primarily observed in the earlier regions of the MTL. Moreover, we demonstrated that voxels exhibiting axis coding supported the transition to region coding and contained information relevant to semantic coding. Together, by providing a detailed characterization of neural object coding schemes and offering a comprehensive summary of visual coding information for each MTL subregion, our results not only emphasize a clear role of the MTL in perceptual processing but also shed light on the translation of perceptiondriven representations of visual features into memory-driven representations of semantics along the MTL processing pathway. [ABSTRACT FROM AUTHOR]

The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the association between social dominance hierarchy status established within cages of group-housed mice and the expression of the stress peptide PACAP in the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also examined the relationship between social dominance rank and blood corticosterone (CORT) levels, body weight, motor coordination (rotorod) and acoustic startle. Male C57BL/6 mice were ranked as either Dominant, Submissive, or Intermediate based on counts of aggressive/submissive encounters assessed at 12 weeks-old following a change in homecage conditions. PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following events where dominance status is recapitulated. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies. [ABSTRACT FROM AUTHOR]

Background: Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD). Objective: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET). Methods: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184. A data driven cut-point for Aβ positivity was defined by Gaussian mixture model of isocortex binding potential (BPND) values. Results: Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aβ-positive. BPND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aβ-positive subjects displayed Aβ binding in striatum, 14 in thalamus and 10 in allocortical regions. Conclusions: Aβ deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring. [ABSTRACT FROM AUTHOR]

Existing research indicates that individuals with Major Depressive Disorder (MDD) exhibit a bias toward salient negative stimuli. However, the impact of such biased stimuli on concurrent cognitive and affective processes in individuals with depression remains inadequately understood. This study aimed to investigate the effects of salient environmental stimuli, specifically emotional faces, on reward-associated processes in MDD. Thirty-three patients with recurrent MDD and thirty-two healthy controls (HC) matched for age, sex, and education were included in the study. We used a reward-related associative learning (RRAL) task primed with emotional (happy, sad, neutral) faces to investigate the effect of salient stimuli on reward-related learning and decision-making in functional magnetic resonance imaging (fMRI). Participants were instructed to ignore emotional faces during the task. The fMRI data were analyzed using a full-factorial general linear model (GLM) in Statistical Parametric Mapping (SPM12). In depressed patients, cues primed with sad faces were associated with reduced amygdala activation. However, both HC and MDD group exhibited reduced ventral striatal activity while learning reward-related cues and receiving rewards. The patients'medication usage was not standardized. This study underscores the functional alteration of the amygdala in response to cognitive tasks presented with negative emotionally salient stimuli in the environment of MDD patients. The observed alterations in amygdala activity suggest potential interconnected effects with other regions of the prefrontal cortex. Understanding the intricate neural connections and their disruptions in depression is crucial for unraveling the complex pathophysiology of the disorder. • An event-related card-guessing task to evaluate neural activation during probabilistic reward learning following brief emotional stimulus was used in the present study. • Both MDD and HC groups showed similar behavioral performance in mean by reaction time, accuracy and learning rates. • Emotional faces induce BOLD changes at the right ventral striatum, suggesting strong affective effect of emotional faces even they were presented very briefly. • In sad face condition, MDD patients had shown significantly reduced BOLD signals in both left and right amygdala and right hippocampus compared to healthy controls. • Emotional priming during probabilistic cue period effects BOLD levels in the right striatum and hippocampus at the outcome period independent from win/lose condition. [ABSTRACT FROM AUTHOR]

Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N < 50). It remains unclear if any alterations are a characteristic of current depression or of past experience of depression, and whether there are MDD-related changes in effective connectivity between the two brain regions. Activations and effective connectivity between the amygdala and dorsolateral prefrontal cortex (DLPFC) in response to fearful face stimuli were studied in a large population-based sample from Generation Scotland. Participants either had no history of MDD (N = 664 in activation analyses, N = 474 in connectivity analyses) or had a diagnosis of MDD during their lifetime (LMDD, N = 290 in activation analyses, N = 214 in connectivity analyses). The within-scanner task involved implicit facial emotion processing of neutral and fearful faces. Compared to controls, LMDD was associated with increased activations in left amygdala (P FWE = 0.031 , k E = 4) and left DLPFC (P FWE = 0.002 , k E = 33), increased mean bilateral amygdala activation (β = 0.0715 , P = 0.0314), and increased inhibition from left amygdala to left DLPFC, all in response to fearful faces contrasted to baseline. Results did not appear to be attributable to depressive illness severity or antidepressant medication status at scan time. Most studied participants had past rather than current depression, average severity of ongoing depression symptoms was low, and a substantial proportion of participants were receiving medication. The study was not longitudinal and the participants were only assessed a single time. LMDD is associated with hyperactivity of the amygdala and DLPFC, and with stronger amygdala to DLPFC inhibitory connectivity, all in response to fearful faces, unrelated to depression severity at scan time. These results help reduce inconsistency in past literature and suggest disruption of 'bottom-up' limbic-prefrontal effective connectivity in depression. • Lifetime MDD is related to higher amygdala and DLPFC activations to fearful faces. • There is increased inhibition from amygdala to DLPFC when viewing fearful faces in LMDD. • Changes are not attributed to acute MDD severity or antidepressant medication status. • Results help substantially reduce ambiguity in the previous depression literature. [ABSTRACT FROM AUTHOR]

Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain. [ABSTRACT FROM AUTHOR]

Introduction: Physical activity influences psychological well-being. This study aimed to determine the impact of exercise intensity on psychological well-being and alterations in emotion-related brain functional connectivity (FC). Methods: Twenty young, healthy, trained athletes performed a low- and highintensity interval exercise (LIIE and HIIE) as well as a control condition in a within-subject crossover design. Before and after each condition, Positive And Negative Affect Scale (PANAS) was assessed as well as resting-state functional MRI (rs-fMRI). Voxel-wise FC was examined for bilateral amygdala seed region to whole-brain and emotion-related anatomical regions (e.g., insula, temporal pole, precuneus). Data analyses were performed using linear mixed-effect models with fixed factors condition and time. Results: The PANAS Positive Affect scale showed a significant increase after LIIE and HIIE and a significant reduction in Negative Affect after the control condition. In rs-fMRI, no significant condition-by-time interactions were observed between the amygdala and whole brain. Amygdala-precuneus FC analysis showed an interaction effect, suggesting reduced post-exercise anticorrelation after the control condition, but stable, or even slightly enhanced anticorrelation for the exercise conditions, especially HIIE. Discussion: In conclusion, both LIIE and HIIE had positive effects on mood and concomitant effects on amygdala-precuneus FC, particularly after HIIE. Although no significant correlations were found between amygdala-precuneus FC and PANAS, results should be discussed in the context of affective disorders in whom abnormal amygdala-precuneus FC has been observed. [ABSTRACT FROM AUTHOR]

Aerobic exercise improves the three stages of emotion regulation: perception, valuation and action. It reduces the perception of negative emotions, encourages individuals to reinterpret emotional situations in a positive or non-emotional manner, and enhances control over emotion expression behaviours. These effects are generated via increased prefrontal cortex activation, the strengthening of functional connections between the amygdala and several other brain regions, and the enhancement of the plasticity of key emotion regulation pathways and nodes, such as the uncinate fasciculus. The effect of aerobic exercise on emotion regulation is influenced by the exercise intensity and duration, and by individuals' exercise experience. Future research may explore the key neural basis of aerobic exercise's promotion of emotion regulation. [ABSTRACT FROM AUTHOR]

High‐frequency oscillations (HFOs) are associated with normal brain function, but are also increasingly recognized as potential biomarkers of epileptogenic tissue. Considering the important role of interneuron activity in physiological HFO generation, we studied their modulation by midazolam (MDZ), an agonist of γ‐aminobutyric acid type A (GABAA)–benzodiazepine receptors. Here, we analyzed 80 intracranial electrode contacts in amygdala and hippocampus of 13 patients with drug‐refractory focal epilepsy who had received MDZ for seizure termination during presurgical monitoring. Ripples (80–250 Hz) and fast ripples (FRs; 250–400 Hz) were compared before and after seizures with MDZ application, and according to their origin either within or outside the individual seizure onset zone (SOZ). We found that MDZ distinctly suppressed all HFOs (ripples and FRs), whereas the reduction of ripples was significantly less pronounced inside the SOZ compared to non‐SOZ contacts. The rate of FRs inside the SOZ was less affected, especially in hippocampal contacts. In a few cases, even a marked increase of FRs following MDZ administration was seen. Our results demonstrate, for the first time, a significant HFO modulation in amygdala and hippocampus by MDZ, thus giving insights into the malfunction of GABA‐mediated inhibition within epileptogenic areas and its role in HFO generation. [ABSTRACT FROM AUTHOR]

This paper explores the challenge of establishing a meaningful connection between a neurotypical therapist and a neurodiverse patient who inhabit different Umwelts, that is, perceptual worlds.1 It discusses how addressing anxiety is crucial in preventing communication difficulties from escalating for individuals with autism who may have heightened stress due to an overgrown amygdala. Embodied mirroring is introduced to focus on perceptions and reduce stress. Furthermore, the potential for epigenetic changes due to unaddressed anxiety is raised. The paper emphasises the importance of responding to individual differences in sensory and perceptual experiences to promote effective communication and positive outcomes in therapy. [ABSTRACT FROM AUTHOR]

The brain regulates every physiological process in the body, including metabolism. Studies investigating brain metabolism have shown that stress can alter major metabolic processes, and that these processes can vary between regions. However, no study has investigated how metabolic pathways may be altered by stressor perception, or whether stress-responsive brain regions can also regulate metabolism. The basolateral amygdala (BLA), a region important for stress and fear, has reciprocal connections to regions responsible for metabolic regulation. In this study, we investigated how BLA influences regional metabolic profiles within the hippocampus (HPC) and medial prefrontal cortex (mPFC), regions involved in regulating the stress response and stress perception, using optogenetics in male C57BL/6 mice during footshock presentation in a yoked shuttlebox paradigm based on controllable (ES) and uncontrollable (IS) stress. RNA extracted from HPC and mPFC were loaded into NanoString® Mouse Neuroinflammation Panels, which also provides a broad view of metabolic processes, for compilation of gene expression profiles. Results showed differential regulation of carbohydrate and lipid metabolism, and insulin signaling gene expression pathways in HPC and mPFC following ES and IS, and that these differences were altered in response to optogenetic excitation or inhibition of the BLA. These findings demonstrate for the first time that individual brain regions can utilize metabolites in a way that are unique to their needs and function in response to a stressor, and that vary based on stressor controllability and influence by BLA. [ABSTRACT FROM AUTHOR]

Reptiles display considerable diversity in reproductive behavior, making them great models to study the neuroendocrine control of reproductive behavior. Many reptile species are seasonally breeding, such that they become reproductively active during their breeding season and regress to a nonreproductive state during their nonbreeding season, with this transition often prompted by environmental cues. In this review, we will focus on summarizing the neural and neuroendocrine mechanisms controlling reproductive behavior. Three major areas of the brain are involved in reproductive behavior: the preoptic area (POA), amygdala, and ventromedial hypothalamus (VMH). The POA and VMH are sexually dimorphic areas, regulating behaviors in males and females respectively, and all three areas display seasonal plasticity. Lesions to these areas disrupt the onset and maintenance of reproductive behaviors, but the exact roles of these regions vary between sexes and species. Different hormones influence these regions to elicit seasonal transitions. Circulating testosterone (T) and estradiol (E2) peak during the breeding season and their influence on reproduction is well‐documented across vertebrates. The conversion of T into E2 and 5α‐dihydrotestosterone can also affect behavior. Melatonin and corticosterone have generally inhibitory effects on reproductive behavior, while serotonin and other neurohormones seem to stimulate it. In general, there is relatively little information on the neuroendocrine control of reproduction in reptiles compared to other vertebrate groups. This review highlights areas that should be considered for future areas of research. Research highlights: Reptiles display considerable diversity in reproductive behavior yet are a relatively understudied group.Reptile reproduction is driven by interactions between brain regions and hormones.Reptilian reproduction is complex, and more research is needed to identify mechanisms across species. [ABSTRACT FROM AUTHOR]

Introduction: Pain is a clinically relevant health care issue with limited therapeutic options, creating the need for new and improved analgesic strategies. The amygdala is a limbic brain region critically involved in the regulation of emotional-affective components of pain and in pain modulation. The central nucleus of amygdala (CeA) serves major output functions and receives nociceptive information via the external lateral parabrachial nucleus (PB). While amygdala neuroplasticity has been linked causally to pain behaviors, non-neuronal pain mechanisms in this region remain to be explored. As an essential part of the neuroimmune system, astrocytes that represent about 40--50% of glia cells within the central nervous system, are required for physiological neuronal functions, but their role in the amygdala remains to be determined for pain conditions. In this study, we measured time-specific astrocyte activation in the CeA in a neuropathic pain model (spinal nerve ligation, SNL) and assessed the effects of astrocyte inhibition on amygdala neuroplasticity and pain-like behaviors in the pain condition. Methods and Results: Glial fibrillary acidic protein (GFAP, astrocytic marker) immunoreactivity and mRNA expression were increased at the chronic (4 weeks post-SNL), but not acute (1 week post-SNL), stage of neuropathic pain. In order to determine the contribution of astrocytes to amygdala pain-mechanisms, we used fluorocitric acid (FCA), a selective inhibitor of astrocyte metabolism. Whole-cell patch-clamp recordings were performed from neurons in the laterocapsular division of the CeA (CeLC) obtained from chronic neuropathic rats. Preincubation of brain slices with FCA (100 µM, 1 h), increased excitability through altered hyperpolarization-activated current (Ih) functions, without significantly affecting synaptic responses at the PB-CeLC synapse. Intra-CeA injection of FCA (100 µM) had facilitatory effects on mechanical withdrawal thresholds (von Frey and paw pressure tests) and emotional-affective behaviors (evoked vocalizations), but not on facial grimace score and anxiety-like behaviors (open field test), in chronic neuropathic rats. Selective inhibition of astrocytes by FCA was confirmed with immunohistochemical analyses showing decreased astrocytic GFAP, but not NeuN, signal in the CeA. Discussion: Overall, these results suggest a complex modulation of amygdala pain functions by astrocytes and provide evidence for beneficial functions of astrocytes in CeA in chronic neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: Cumulative evidence suggests that sensory cortices interact with the basolateral amygdala (BLA) defense circuitry to mediate threat conditioning, memory retrieval, and extinction learning. The olfactory piriform cortex (PC) has been posited as a critical site for olfactory associative memory. Recently, we have shown that N-methyl-D-aspartate receptor (NMDAR)-dependent plasticity in the PC critically underpins olfactory threat extinction. Aging-associated impairment of olfactory threat extinction is related to the hypofunction of NMDARs in the PC. Methods: In this study, we investigated activation of neuronal cFos and epigenetic marks in the BLA and PC using immunohistochemistry, following olfactory threat conditioning and extinction learning in rats. Results: We found highly correlated cFos activation between the posterior PC (pPC) and BLA. cFos was correlated with the degree of behavioral freezing in the pPC in both adult and aged rats, and in the BLA only in adult rats. Markers of DNA methylation 5 mC and histone acetylation H3K9/K14ac, H3K27ac, and H4ac exhibited distinct training-, region-, and age-dependent patterns of activation. Strong correlations of epigenetic marks between the BLA and pPC in adult rats were found to be a general feature. Conversely, aged rats only exhibited correlations of H3 acetylations between the two structures. Histone acetylation varied as a function of aging, revealed by a reduction of H3K9/K14ac and an increase of H4ac in aged brains at basal condition and following threat conditioning. Discussion: These findings underscore the coordinated role of PC and BLA in olfactory associative memory storage and extinction, with implications for understanding aging related cognitive decline. [ABSTRACT FROM AUTHOR]

While colloquially recognized for its role in pleasure, reward, and affect, dopamine is also necessary for proficient action control. Many motor studies focus on dopaminergic transmission along the nigrostriatal pathway, using Parkinson's disease as a model of a dorsal striatal lesion. Less attention to the mesolimbic pathway and its role in motor control has led to an important question related to the limbic–motor network. Indeed, secondary targets of the mesolimbic pathway include the hippocampus and amygdala, and these are linked to the motor cortex through the substantia nigra and thalamus. The modulatory impact of dopamine in the hippocampus and amygdala in humans is a focus of current investigations. This review explores dopaminergic activity in the mesial temporal lobe by summarizing dopaminergic networks and transmission in these regions and examining their role in behaviour and disease. [ABSTRACT FROM AUTHOR]

The use of predators and predator odor as stressors is an important and ecologically relevant model for studying the impact of behavioral responses to threat. Here we summarize neural substrates and behavioral changes in rats resulting from predator exposure. We briefly define the impact predator exposure has on neural targets throughout development (neonatal, juvenile, and adulthood). These findings allow us to conceptualize the impact of predator exposure in the brain, which in turn may have broader implications for human disorders such as PTSD. Importantly, inclusion of sex as a biological variable yields distinct results that may indicate neural substrates impacted by predator exposure differ based on sex. [ABSTRACT FROM AUTHOR]

Background: Melancholic depression (MD) is one of the most prevalent and severe subtypes of major depressive disorder (MDD). Previous studies have revealed inconsistent results regarding alterations in grey matter volume (GMV) of the hippocampus and amygdala of MD patients, possibly due to overlooking the complexity of their internal structure. The hippocampus and amygdala consist of multiple and functionally distinct subregions, and these subregions may play different roles in MD. This study aims to investigate the volumetric alterations of each subregion of the hippocampus and amygdala in patients with MD and non-melancholic depression (NMD). Methods: A total of 146 drug-naïve, first-episode MDD patients (72 with MD and 74 with NMD) and 81 gender-, age-, and education-matched healthy controls (HCs) were included in the study. All participants underwent magnetic resonance imaging (MRI) scans. The subregional segmentation of hippocampus and amygdala was performed using the FreeSurfer 6.0 software. The multivariate analysis of covariance (MANCOVA) was used to detect GMV differences of the hippocampal and amygdala subregions between three groups. Partial correlation analysis was conducted to explore the relationship between hippocampus or amygdala subfields and clinical characteristics in the MD group. Age, gender, years of education and intracranial volume (ICV) were included as covariates in both MANCOVA and partial correlation analyses. Results: Patients with MD exhibited a significantly lower GMV of the right hippocampal tail compared to HCs, which was uncorrelated with clinical characteristics of MD. No significant differences were observed among the three groups in overall and subregional GMV of amygdala. Conclusions: Our findings suggest that specific hippocampal subregions in MD patients are more susceptible to volumetric alterations than the entire hippocampus. The reduced right hippocampal tail may underlie the unique neuropathology of MD. Future longitudinal studies are required to better investigate the associations between reduced right hippocampal tail and the onset and progression of MD. [ABSTRACT FROM AUTHOR]

Music is powerful in conveying emotions and triggering affective brain mechanisms. Affective brain responses in previous studies were however rather inconsistent, potentially because of the non-adaptive nature of recorded music used so far. Live music instead can be dynamic and adaptive and is often modulated in response to audience feedback to maximize emotional responses in listeners. Here, we introduce a setup for studying emotional responses to live music in a closed-loop neurofeedback setup. This setup linked live performances by musicians to neural processing in listeners, with listeners' amygdala activity was displayed to musicians in real time. Brain activity was measured using functional MRI, and especially amygdala activity was quantified in real time for the neurofeedback signal. Live pleasant and unpleasant piano music performed in response to amygdala neurofeedback from listeners was acoustically very different from comparable recorded music and elicited significantly higher and more consistent amygdala activity. Higher activity was also found in a broader neural network for emotion processing during live compared to recorded music. This finding included observations of the predominance for aversive coding in the ventral striatum while listening to unpleasant music, and involvement of the thalamic pulvinar nucleus, presumably for regulating attentional and cortical flow mechanisms. Live music also stimulated a dense functional neural network with the amygdala as a central node influencing other brain systems. Finally, only live music showed a strong and positive coupling between features of the musical performance and brain activity in listeners pointing to real-time and dynamic entrainment processes. [ABSTRACT FROM AUTHOR]

Adaptation aftereffects—in which prolonged prior experience (adaptation) can bias the subsequent judgment of ambiguous stimuli—are a ubiquitous phenomenon. Numerous studies have found behaviorally stable adaptation aftereffects in a variety of areas. However, it is unclear which brain regions are responsible for this function, particularly in the case of high-level emotional adaptation aftereffects. To address this question, the present study used fMRI technology to investigate the neural mechanism of emotional adaptation aftereffects. Consistent with previous studies, we observed typical emotional adaptation effects in behavior. Specifically, for the same morphed facial images, participants perceived increased sadness after adapting to a happy facial image and increased happiness after adapting to a sad facial image. More crucially, by contrasting neural responses to ambiguous morphed facial images (i.e., facial images of intermediate morph levels) following adaptation to happy and sad expressions, we demonstrated a neural mechanism of emotional aftereffects supported by the left amygdala/insula, right angular gyrus, and right inferior frontal gyrus. These results suggest that the aftereffects of emotional adaptation are supported not only by brain regions subserving emotional processing but also by those subserving cognitive control. [ABSTRACT FROM AUTHOR]

Animals have a sleep cycle that involves the repetitive occurrence of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. In a previous study, we discovered that a transient increase in dopamine (DA) levels in the basolateral amygdala (BLA) during NREM sleep terminates NREM sleep and initiates REM sleep by acting on Drd2 -positive neurons (Hasegawa et al., 2022). In this study, we identified the neurons activated by the transient increase of DA in the BLA and found that chemogenetic excitation of these neurons increased REM sleep. Additionally, we demonstrated that acute inhibition of serotonin (5HT) in the BLA elicited a transient increase in DA in the BLA, which triggered REM sleep. • Re-activation of the neurons activated by the transient increase of DA in the BLA increased REM sleep. • Inhibition of serotonin (5HT) fibers in the BLA, but not in the VTA, elicited a transient increase in DA, which triggered REM sleep. • These observations suggest that a decrease in 5HT tone in the BLA during NREM sleep causes an increase in DA, triggering REM sleep. [ABSTRACT FROM AUTHOR]

Studies of affective neuroscience have typically employed highly controlled, static experimental paradigms to investigate the neural underpinnings of threat and reward processing in the brain. Yet our knowledge of affective processing in more naturalistic settings remains limited. Specifically, affective studies generally examine threat and reward features separately and under brief time periods, despite the fact that in nature organisms are often exposed to the simultaneous presence of threat and reward features for extended periods. To study the neural mechanisms of threat and reward processing under distinct temporal profiles, we created a modified version of the PACMAN game that included these environmental features. We also conducted two automated meta‐analyses to compare the findings from our semi‐naturalistic paradigm to those from more constrained experiments. Overall, our results revealed a distributed system of regions sensitive to threat imminence and a less distributed system related to reward imminence, both of which exhibited overlap yet neither of which involved the amygdala. Additionally, these systems broadly overlapped with corresponding meta‐analyses, with the notable absence of the amygdala in our findings. Together, these findings suggest a shared system for salience processing that reveals a heightened sensitivity toward environmental threats compared to rewards when both are simultaneously present in an environment. The broad correspondence of our findings to meta‐analyses, consisting of more tightly controlled paradigms, illustrates how semi‐naturalistic studies can corroborate previous findings in the literature while also potentially uncovering novel mechanisms resulting from the nuances and contexts that manifest in such dynamic environments. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) can potentially disrupt neurotransmitters activities in the central nervous system (CNS) and cause neurotoxicity through various pathways. These pathways include increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis. In this study, we investigated the long-term effects of METH addiction on the structural changes in the amygdala of postmortem human brains and the involvement of the brain-cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF) and Akt-1/GSK3 signaling pathways. We examined ten male postmortem brains, comparing control subjects with chronic METH users, using immunohistochemistry, real-time polymerase chain reaction (to measure levels of CREB, BDNF, Akt-1, GSK3, and tumor necrosis factor-a [TNF-a]), Tunnel assay, stereology, and assays for reactive oxygen species (ROS), glutathione disulfide (GSSG), and glutathione peroxidase (GPX). The findings revealed that METH significantly reduced the expression of BDNF, CREB, Akt-1, and GPX while increasing the levels of GSSG, ROS, RIPK3, GSK3, and TNF-a. Furthermore, METH-induced inflammation and neurodegeneration in the amygdala, with ROS production mediated by the CREB/BDNF and Akt-1/GSK3 signaling pathways. [ABSTRACT FROM AUTHOR]

Our data demonstrated brain region-specific microglial heterogeneity in young and old mice. In addition, sleep deprivation (SD) disrupted microglia and behaviors in an age-specific manner. Microglial density in the brain is significantly positively correlated with SD-induced hyperactivity in young mice. Contrarily, negative correlations are shown between the microglial density and behaviors in vehicle-treated young and old mice. [Display omitted] • Brain region-specific microglial heterogeneity in young and old mice. • Sleep deprivation disrupts microglia and behaviors in an age-specific manner. • Microglial density is positively correlated with SD-induced behaviors in youngs. • Microglial density is negatively correlated with behaviors in young and old mice. Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD. [ABSTRACT FROM AUTHOR]

Animal models suggest that experiencing high-stress levels induces changes in amygdalar circuitry and gene expression. In humans, combat exposure has been shown to alter amygdalar responsivity and connectivity, but abnormalities have been indicated to normalize at least partially upon the termination of stress exposure. In contrast, other evidence suggests that combat exposure continues to exert influence on exposed individuals well beyond deployment and homecoming, as indicated by longitudinal psychosocial evidence from veterans, and observation of greater health decline in veterans late in life. Accordingly, the experience of combat stress early in life may affect amygdalar responsivity late in life, a possibility requiring careful consideration of the confounding effects of aging, genetic factors, and symptoms of post-traumatic stress disorder. Here, we investigated amygdalar responsivity in a unique sample of 16 male monozygotic (MZ) twin pairs in their sixties, where one but not the other sibling had been exposed to combat stress in early adulthood. Forty years after combat experience, a generally blunted amygdalar response was observed in combat-exposed veterans compared to their non-exposed twin siblings. Spatial associations between these phenotypical changes and patterns of gene expression in the brain were found for genes involved in the synaptic organization and chromatin structure. Protein-protein interactions among the set of identified genes pointed to histone modification mechanisms. We conclude that exposure to combat stress early in life continues to impact brain function beyond the termination of acute stress and appears to exert prolonged effects on amygdalar function later in life via neurogenetic mechanisms. [ABSTRACT FROM AUTHOR]

The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer's disease in the seminal 1991 article by Braak and Braak. This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer's disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer's disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer's disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Systemic inflammatory response syndrome (SIRS) is a potentially fatal reaction to various forms of tissue damage and infections that cause damage to various organs. Furthermore, the brain is damaged earlier than other organs, resulting in diffuse brain dysfunction. The central clinical symptom of SIRS is delirium and emotional changes are involved in disease development. Although the amygdala is known to play a major role, the mechanisms underlying emotional changes in the early stages of SIRS have not been elucidated. Therefore, changes to dopamine levels in the amygdala were observed using an in vivo model of lipopolysaccharide (LPS)- induced SIRS to clarify the biochemical mechanisms activated in the early stages of SIRS. Extracellular dopamine was collected from the amygdala of free moving rats via microdialysis and then analyzed by high-performance liquid chromatography. In addition, emotional changes were assessed with the open field and sucrose preference tests. In the LPS group, dopamine release in the amygdala increased remarkably immediately after LPS administration, peaking at 120 min. Thereafter, dopamine release temporarily decreased, but then significantly increased again after 180 min. The present results suggest that diffuse brain dysfunction in the early stages of SIRS may involve altered dopamine levels in the amygdala. [ABSTRACT FROM AUTHOR]

We outline how a predictive processing framework based on active inference can help overcome the limitations of fragmented feed-forward processing theories and more comprehensively explain the role of the amygdala in anxiety, fear, and danger detection. This framework integrates theoretical predictions with empirical findings, suggesting that the central amygdala subnucleus acts as a Bayesian regulator of an interoceptive self-model, sending top-down predictions to the basolateral amygdala for efficient perception. Fear conditioning is discussed as an example of proactive homeostatic regulation, where exteroceptive cues are used to anticipate negative interoceptive experiences. By extension, other amygdala functions (e.g., its role in approach/avoidance behavior or attention) can be explained using the same computational principles within a hierarchical active inference model. The amygdala is a heterogeneous network of subcortical nuclei with central importance in cognitive and clinical neuroscience. Various experimental designs in human psychology and animal model research have mapped multiple conceptual frameworks (e.g., valence/salience and decision making) to ever more refined amygdala circuitry. However, these predominantly bottom up-driven accounts often rely on interpretations tailored to a specific phenomenon, thus preventing comprehensive and integrative theories. We argue here that an active inference model of amygdala function could unify these fractionated approaches into an overarching framework for clearer empirical predictions and mechanistic interpretations. This framework embeds top-down predictive models, informed by prior knowledge and belief updating, within a dynamical system distributed across amygdala circuits in which self-regulation is implemented by continuously tracking environmental and homeostatic demands. [ABSTRACT FROM AUTHOR]

Rationale: Relapse into substance use is often triggered by exposure to drug-related environmental cues. The magnitude of drug seeking depends on the duration of abstinence, a phenomenon known as the incubation of drug craving. Clinical and preclinical research shows that the insular cortex is involved in substance use disorders and cue-induced drug seeking. However, the role of the insula on memory retrieval and motivational integration for cue-elicited drug seeking remains to be determined. Objectives: We investigated the role of the anterior insular cortex (aIC) and its glutamatergic projection to amygdala nuclei (aIC-AMY) on the expression of conditioned place preference (CPP) during early and late abstinence. Methods: Male adult C57BL/6J mice underwent amphetamine-induced CPP, and their preference was tested following 1 or 14 days of abstinence. aIC and aIC-AMY functional role in CPP expression was assessed at both abstinence periods by employing optogenetic silencing and behavioral pharmacology. Results: Compared to a single day, an exacerbated preference for the amphetamine-paired context was observed after 14 days of abstinence. Photoinhibition of either aIC or aIC-AMY projection reduced CPP expression following late but not early abstinence. Similarly, the antagonism of aIC NMDA receptors reduced CPP expression after 14 days of abstinence but not 1 day. Conclusions: These results suggest that aIC and its glutamatergic output to amygdala nuclei constitute critical neurobiological substrates mediating enhanced motivational cue reactivity during the incubation of amphetamine craving rather than contextual memory recall. Moreover, cortical NMDA receptor signaling may become sensitized during abstinence, ultimately modulating disproportioned drug seeking. [ABSTRACT FROM AUTHOR]

Amygdala atypical volume development and functional connectivity (FC) at small gestational ages (GA) have been found across childhood. This adult-oriented study assesses whether altered amygdala structure and function is present following low-risk preterm birth. T1-weighted and resting-state functional MRI images of 33 low-risk preterm (30–36 weeks' GA) and 29 full-term (37–42 weeks' GA) young adults of both sexes, aged between 20 and 32 years old, were analyzed using FreeSurfer (v6.0.0) and Coon Toolbox (v21.a). The social-emotional assessment included Happé's Strange Stories Test, the Moral Judgment Test, Delay-Discounting Test, Adult Self Report, and Emotion Regulation Questionnaire. No differences were found in social-emotional outcomes or amygdala volumes between the groups. Low-risk preterm young adults showed increased FC between the left amygdala, right amygdala and medial frontal cortex (MedFC) (F = 9.89, p-FWE = 0.009) at cluster level compared to their full-term peers. However, significant results at connection level were not observed between left and right amygdala. Lastly, increased FC at cluster level between the right amygdala and MedFC, and left amygdala and MedFC, was related to better social-emotional outcomes only in low-risk preterm young adults (F = 6.60, p-FWE = 0.036) at cluster level. At connection level, in contrast, only right amygdala–MedFC increased FC was significantly associated with better social-emotional outcomes. This study reveals that low-risk prematurity does not have an effect on social-emotional outcomes or structural amygdala volumes during young adulthood. However, individuals who were considered to be at a lower risk of exhibiting neurodevelopmental alterations following preterm birth demonstrated increased FC between the left and right amygdala and MedFC. [ABSTRACT FROM AUTHOR]

Current noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. We investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS' effects on amygdala-fear circuit resting-state functional connectivity. Thirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. Compared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F (1,25) = 4.86, p = 0.04, η2 = 0.16) during the fear task, and lower hippocampal (F (1,27) = 4.41, p = 0.05, η2 = 0.14), and dorsal anterior cingulate cortex (F (1,27) = 6.26, p = 0.02; η2 = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F (1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F (1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F (1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F (1,28) = 3.52, p = 0.05) resting-state functional connectivity. tFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS' therapeutic potential for individuals with clinical levels of anxiety. • Transcranial Focused Ultrasound can noninvasively modulate the amygdala in humans. • tFUS decreased amygdala fear task activation associated with decreased anxiety. • tFUS decreased amygdala resting-state connectivity with the insula and hippocampus. • tFUS increased amygdala-ventromedial prefrontal cortex resting-state connectivity. • Future studies should investigate tFUS' therapeutic potential for anxiety disorders. [ABSTRACT FROM AUTHOR]