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It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating can become maladaptive. Currently, the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance. [ABSTRACT FROM AUTHOR]

Objective: Temporal lobe epilepsy (TLE) accompanied by hippocampal sclerosis (HS) is the most common type of focal epilepsies. Hemispheric asymmetry is a feature of brain organization in both invertebrates and vertebrates and may be the key to some neurodegenerative diseases. In this context, we aimed to investigate the volumetric asymmetry difference in cerebral structures between TLE patients and the healthy control group, based on magnetic resonance imaging (MRI) data that may be used as a new neuroimaging marker for TLE cases. Patients and Methods: In this retrospective study the cranial MRIs of fourteen clinically manifesting, radiologically HS-identified, and diagnosed TLE patients and fourteen healthy individuals from the Radiology Department of Yeditepe University Hospital were evaluated. Volume measurements and asymmetry index (AI) calculations in the total brain, hippocampus, temporal lobe, amygdala, thalamus, nucleus accumbens (NAc), premotor cortex, primary and somatosensory cortices were performed using the medical NeuroQuant® software. A negative AI value represented asymmetry towards the right due to reduced left hemispheric volume; a positive AI value represented asymmetry towards the left due to reduced right hemispheric volume. Subsequently, differences in volume and asymmetric patterns were investigated among TLE subgroups (right and left-sided TLE) and controls. Results: The left-sided TLE patients showed significant bilateral total brain volume reduction compared to the control group. Significant ipsilateral volumetric declines were also detected in the premotor cortex, the temporal lobe, and NAc with remarkable asymmetry to the right side. No significant changes were detected in right-sided TLE patients compared to the other groups. Conclusion: Overall, findings suggest that TLE patients had volumetric alterations with symmetry changes beyond the mesial temporal structures. With further investigations, the asymmetry measures can provide additional knowledge for TLE diagnosis. [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]

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]

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague–Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar–Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy. [ABSTRACT FROM AUTHOR]

Background: There are phenomenological similarities between social anxiety disorder (SAD) and posttraumatic stress disorder, such as a provoking aversive event, posttraumatic stress symptoms (e.g. intrusions) in response to these events and deficient (context-dependent) fear conditioning processes. This study investigated the neural correlates of context-dependent extinction recall and fear renewal in SAD, specifically in patients with intrusions in response to an etiologically relevant aversive social event. Methods: During functional magnetic resonance imaging a two-day context-dependent fear conditioning paradigm was conducted in 54 patients with SAD and 54 healthy controls (HC). This included fear acquisition (context A) and extinction learning (context B) on one day, and extinction recall (context B) as well as fear renewal (contexts C and A) one day later. The main outcome measures were blood oxygen level-dependent responses in regions of interest and skin conductance responses. Results: Patients with SAD showed reduced differential conditioned amygdala activation during extinction recall in the safe extinction context and during fear renewal in the acquisition context compared to HC. Patients with clinically relevant intrusions moreover exhibited hypoactivation of the ventromedial prefrontal cortex (vmPFC) during extinction learning, extinction recall, and fear renewal in a novel context, while amygdala activation more strongly decreased during extinction learning and increased during fear renewal in the acquisition context compared with patients without intrusions. Conclusions: Our study provides first evidence that intrusions in SAD are associated with similar deficits in context-dependent regulation of conditioned fear via the vmPFC as previously demonstrated in posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]

Autophagy is a conserved lysosomal degradation process that has recently been found to be associated with stress-related psychological diseases. However, previous studies have yielded inconsistent results regarding the effects of various stress patterns on autophagy in different brain regions. This discrepancy may arise from differences in autophagy flux across nuclei, the type of stress experienced, and the timing of autophagy assessment after stress exposure. In this study, we assessed autophagy flux in the rat hippocampus (HPC), medial prefrontal cortex (mPFC), and basal lateral amygdala (BLA) by quantifying protein levels of p-ULK1, LC3-I, LC3-II, and p62 via Western blot analysis at 15 min, 30 min, and 60 min following various stress paradigms: restraint stress, foot shock, single corticosterone injection, and chronic corticosterone treatment. We found that: (1) hippocampal autophagy decreased within 1 h of restraint stress, foot shock, and corticosterone injection, except for a transient increase at 30 min after restraint stress; (2) autophagy increased 1 h after restraint stress and corticosterone injection but decreased 1 h after foot shock in mPFC; (3) In BLA, autophagy increased 1 h after foot shock and corticosterone injection but decreased 1 h after restraint stress; (4) Chronic corticosterone increased autophagy in mPFC and BLA but had no effects in HPC. These findings suggest that stress regulates autophagy in a brain region- and stressor-specific manner within 1 h after stress exposure, which may contribute to the development of stress-related psychological disorders. [ABSTRACT FROM AUTHOR]

The multiple-memory-systems framework—that distinct types of memory are supported by distinct brain systems—has guided learning and memory research for decades. However, recent work challenges the one-to-one mapping between brain structures and memory types central to this taxonomy, with key memory-related structures supporting multiple functions across substructures. Here we integrate cross-species findings in the hippocampus, striatum, and amygdala to propose an updated framework of multiple memory subsystems (MMSS). We provide evidence for two organizational principles of the MMSS theory: First, opposing memory representations are colocated in the same brain structures; second, parallel memory representations are supported by distinct structures. We discuss why this burgeoning framework has the potential to provide a useful revision of classic theories of long-term memory, what evidence is needed to further validate the framework, and how this novel perspective on memory organization may guide future research. [ABSTRACT FROM AUTHOR]

In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association. [ABSTRACT FROM AUTHOR]

By affecting core neurobiological systems early in development, early life adversities (ELAs) might confer latent vulnerability to future psychopathologies. This coordinate-based meta-analysis aims to identify significant convergent alterations in functional connectivity of the amygdala related to ELAs across resting-state and task-based fMRI-studies. Five electronic databases were systematically searched until 22 October 2020, retrieving 49 eligible studies (n = 3162 participants). Convergent alterations in functional connectivity related to ELAs between the amygdala and the anterior cingulate cortex (ACC) and left hippocampus were found. Sub-analyses based on hemisphere and direction showed that connectivity seeded in the right amygdala was affected and, moreover, revealed that connectivity with ACC was decreased. Analyses based on paradigm and age showed that amygdala-ACC coupling was altered during resting state and that amygdala–left hippocampus connectivity was mostly affected during task-based paradigms and in adult participants. While both regions showed altered connectivity during emotion processing and following adverse social postnatal experiences such as maltreatment, amygdala-ACC coupling was mainly affected when ELAs were retrospectively assessed through self-report. We show that ELAs are associated with altered functional connectivity of the amygdala with the ACC and hippocampus. As such, ELAs may embed latent vulnerability to future psychopathologies by systematically affecting important neurocognitive systems. [ABSTRACT FROM AUTHOR]

This study focuses on hippocampal and amygdala volume, seed-based connectivity, and psychological traits of Holocaust survivors who experienced stress during prenatal and early postnatal development. We investigated people who lived in Central Europe during the Holocaust and who, as Jews, were in imminent danger. The group who experienced stress during their prenatal development and early postnatal (PreP) period (n = 11) were compared with a group who experienced Holocaust-related stress later in their lives: in late childhood, adolescence, and early adulthood (ChA) (n = 21). The results of volumetry analysis showed significantly lower volumes of both hippocampi and the right amygdala in the PreP group. Seed-based connectivity analysis revealed increased connectivity from the seed in the right amygdala to the middle and posterior cingulate cortex, caudate, and inferior left frontal operculum in the PreP group. Psychological testing found higher levels of traumatic stress symptoms (TCS-40) and lower levels of well-being (SOS-10) in the PreP group than in the ChA group. The results of our study demonstrate that extreme stress experienced during prenatal and early postnatal life has a profound lifelong impact on the hippocampus and amygdala and on several psychological characteristics. [ABSTRACT FROM AUTHOR]

The importance of amygdala, hippocampus, and medial prefrontal cortex (mPFC) for the integration of neural, endocrine, and affective stress processing was shown in healthy participants and patients with stress-related disorders. The present manuscript which reports on one study-arm of the LawSTRESS project, aimed at investigating the predictive value of acute stress responses in these regions for biopsychological consequences of chronic stress in daily life. The LawSTRESS project examined law students either in preparation for their first state examination (stress group [SG]) or in the mid-phase of their study program (control group [CG]) over 13 months. Ambulatory assessments comprising perceived stress measurements and the cortisol awakening response (CAR) were administered on six sampling points (t1 = − 1 year, t2 = − 3 months, t3 = − 1 week, t4 = exam, t5 = + 1 week, t6 = + 1 month). In a subsample of 124 participants (SG: 61; CG: 63), ScanSTRESS was applied at baseline. In the SG but not in the CG, amygdala, hippocampus, and (post-hoc analyzed) right mPFC activation changes during ScanSTRESS were significantly associated with the trajectory of perceived stress but not with the CAR. Consistent with our finding in the total LawSTRESS sample, a significant increase in perceived stress and a blunted CAR over time could be detected in the SG only. Our findings suggest that more pronounced activation decreases of amygdala, hippocampus, and mPFC in response to acute psychosocial stress at baseline were related to a more pronounced increase of stress in daily life over the following year. [ABSTRACT FROM AUTHOR]

Background: Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. Methods: We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. Results: Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31–40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. Conclusion: We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research. [ABSTRACT FROM AUTHOR]

This correction notice addresses errors in an article titled "Changes in responses of the amygdala and hippocampus during fear conditioning are associated with persecutory beliefs." The original version of the article contained errors in the Introduction, Methods, Clinical measures, Discussion, and other sections. The corrected version provides accurate information about subclinical psychotic symptoms, the recruitment of participants, measurement of persecutory beliefs, main findings, fear conditioning responses in the human medial temporal lobe, animal models of psychosis, and additional future directions. The original article has been corrected. [Extracted from the article]

This article discusses the role of the amygdala and hippocampus in emotional imagery. It challenges the notion that the amygdala is consistently activated during emotional processing, suggesting that conflicting results may be due to variations in task design and the proximity of the amygdala to other activated regions. The article presents evidence that the anterior hippocampus, rather than the amygdala, may play a key role in emotional processing in some contexts. The authors recommend including an amygdala perceptual localizer task and using sagittal views in future studies to accurately assess and confirm amygdala involvement. [Extracted from the article]

Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2‐positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl‐stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate‐lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate‐lesioned monkeys but no differences were found in layer II of area 36. In adult‐lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age‐dependent manner. [ABSTRACT FROM AUTHOR]

By affecting core neurobiological systems early in development, early life adversities (ELAs) might confer latent vulnerability to future psychopathologies. This coordinate-based meta-analysis aims to identify significant convergent alterations in functional connectivity of the amygdala related to ELAs across resting-state and task-based fMRI-studies. Five electronic databases were systematically searched until 22 October 2020, retrieving 49 eligible studies (n = 3162 participants). Convergent alterations in functional connectivity related to ELAs between the amygdala and the anterior cingulate cortex (ACC) and left hippocampus were found. Sub-analyses based on hemisphere and direction showed that connectivity seeded in the right amygdala was affected and, moreover, revealed that connectivity with ACC was decreased. Analyses based on paradigm and age showed that amygdala-ACC coupling was altered during resting state and that amygdala–left hippocampus connectivity was mostly affected during task-based paradigms and in adult participants. While both regions showed altered connectivity during emotion processing and following adverse social postnatal experiences such as maltreatment, amygdala-ACC coupling was mainly affected when ELAs were retrospectively assessed through self-report. We show that ELAs are associated with altered functional connectivity of the amygdala with the ACC and hippocampus. As such, ELAs may embed latent vulnerability to future psychopathologies by systematically affecting important neurocognitive systems. [ABSTRACT FROM AUTHOR]

In recent years, with the development of technology, three-dimensional software has entered our lives. Volumetric measurements made with Magnetic Resonance Imaging (MRI) are essential in the morphometry of the brain and subcortical structures. In this study, we aim to share the volume and asymmetry of the hippocampus, its sub-branches, and other subcortical structures and their interaction with age/sex using volBrain, a web-based automated software. 1.5 T T1-weighted volumetric MRI, of 90 healthy individuals (51 females, 39 males) of both genders were included in our study. Pallidum, hippocampus, Cornu Ammonis1 (CA1), Cornu Ammonis2-3 (CA2-CA3), and Cornu Ammonis4-Dentate Gyrus (CA4-DG) measurements in females and males had a statistically higher mean in the right region (p < 0.05). In addition, females' hippocampus, CA1, CA2-CA3, and CA4-DG averages decreased more rapidly in the right region than in the left region. Subiculum measurement had a higher mean in the left region in both males and females (p < 0.05). The mean subiculum of males decreased more rapidly in the right region than in the left region. When the total values of the subcortical region in males and females were compared according to age categories, amygdala, pallidum, putamen, hippocampus, CA2-CA3, and subiculum values did not differ to gender in individuals aged 50 and over (p > 0.05). In individuals under 50 years old, the mean of females was statistically lower than the mean of males (p < 0.05). The Stratum radiatum (SR), Stratum lacunosum (SL), and Stratum molecuare (SM) asymmetry values of males in the examined subcortical regions had a higher mean than females (p = 0.039). In other regions, there was no statistically asymmetrical difference (p > 0.05). Studies evaluating the volumetric analysis and asymmetry of hippocampus subbranches and other subcortical structures in adults are very limited. As a result, the morphometry of the hippocampus subbranches and other subcortical structures was examined in detail. It was determined that the structures differed according to age, gender and body side. [ABSTRACT FROM AUTHOR]

This study focuses on hippocampal and amygdala volume, seed-based connectivity, and psychological traits of Holocaust survivors who experienced stress during prenatal and early postnatal development. We investigated people who lived in Central Europe during the Holocaust and who, as Jews, were in imminent danger. The group who experienced stress during their prenatal development and early postnatal (PreP) period (n = 11) were compared with a group who experienced Holocaust-related stress later in their lives: in late childhood, adolescence, and early adulthood (ChA) (n = 21). The results of volumetry analysis showed significantly lower volumes of both hippocampi and the right amygdala in the PreP group. Seed-based connectivity analysis revealed increased connectivity from the seed in the right amygdala to the middle and posterior cingulate cortex, caudate, and inferior left frontal operculum in the PreP group. Psychological testing found higher levels of traumatic stress symptoms (TCS-40) and lower levels of well-being (SOS-10) in the PreP group than in the ChA group. The results of our study demonstrate that extreme stress experienced during prenatal and early postnatal life has a profound lifelong impact on the hippocampus and amygdala and on several psychological characteristics. [ABSTRACT FROM AUTHOR]

Distinct neural effects of threat versus deprivation emerge by childhood, but little data are available in infancy. Withdrawn versus negative parenting may represent dimensionalized indices of early deprivation versus early threat, but no studies have assessed neural correlates of withdrawn versus negative parenting in infancy. The objective of this study was to separately assess the links of maternal withdrawal and maternal negative/inappropriate interaction with infant gray matter volume (GMV), white matter volume (WMV), amygdala, and hippocampal volume. Participants included 57 mother‐infant dyads. Withdrawn and negative/inappropriate aspects of maternal behavior were coded from the Still‐Face Paradigm at four months infant age. Between 4 and 24 months (M age = 12.28 months, SD = 5.99), during natural sleep, infants completed an MRI using a 3.0 T Siemens scanner. GMV, WMV, amygdala, and hippocampal volumes were extracted via automated segmentation. Diffusion weighted imaging volumetric data were also generated for major white matter tracts. Maternal withdrawal was associated with lower infant GMV. Negative/inappropriate interaction was associated with lower overall WMV. Age did not moderate these effects. Maternal withdrawal was further associated with reduced right hippocampal volume at older ages. Exploratory analyses of white matter tracts found that negative/inappropriate maternal behavior was specifically associated with reduced volume in the ventral language network. Results suggest that quality of day‐to‐day parenting is related to infant brain volumes during the first two years of life, with distinct aspects of interaction associated with distinct neural effects. [ABSTRACT FROM AUTHOR]

In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association. [ABSTRACT FROM AUTHOR]

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated. [ABSTRACT FROM AUTHOR]

Background: Although many previous studies reported structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy (ECT) in major depressive disorder (MDD), yet the exact roles of both areas for antidepressant effects are still controversial. Methods: In the current study, segmentation of amygdala and hippocampal sub-regions was used to investigate the longitudinal changes of volume, the relationship between volume and antidepressant effects, and prediction performances for ECT in MDD patients before and after ECT using two independent datasets. Results: As a result, MDD patients showed selectively and consistently increased volume in the left lateral nucleus, right accessory basal nucleus, bilateral basal nucleus, bilateral corticoamygdaloid transition (CAT), bilateral paralaminar nucleus of the amygdala, and bilateral hippocampus-amygdala transition area (HATA) after ECT in both datasets, whereas marginally significant increase of volume in bilateral granule cell molecular layer of the head of dentate gyrus, the bilateral head of cornu ammonis (CA) 4, and left head of CA 3. Correlation analyses revealed that increased volume of left HATA was significantly associated with antidepressant effects after ECT. Moreover, volumes of HATA in the MDD patients before ECT could be served as potential biomarkers to predict ECT remission with the highest accuracy of 86.95% and 82.92% in two datasets (The predictive models were trained on Dataset 2 and the sensitivity, specificity and accuracy of Dataset 2 were obtained from leave-one-out-cross-validation. Thus, they were not independent and very likely to be inflated). Conclusions: These results not only suggested that ECT could selectively induce structural plasticity of the amygdala and hippocampal sub-regions associated with antidepressant effects of ECT in MDD patients, but also provided potential biomarkers (especially HATA) for effectively and timely interventions for ECT in clinical applications. [ABSTRACT FROM AUTHOR]

The core symptoms of Autism Spectrum Disorder (ASD) are impairments in social interaction/communication and the presence of stereotyped and repetitive behaviour. The amygdala and hippocampus are involved in core functions in the "social brain" and, thus, may be of particular interest in ASD. Previous studies demonstrated inconsistent results, revealing both increased and reduced volume of these brain structures in individuals with ASD. In this study, we investigated the grey and white matter volumes of amygdala and hippocampus in primary-school-aged children with and without ASD. Also, we assessed the relationships between the volume of brain structures and behavioural measures in children with ASD. A total of 36 children participated in the study: 18 children with ASD (13 boys, age range 8.01–14.01 years, mean age (Mage) = 10.02, standard deviation (SD) = 1.76) and 18 age- and sex-matched typically developing controls (13 boys, age range 7.06–12.03 years, Mage = 10.00, SD = 1.38). The whole-brain structural magnetic resonance imaging (MRI) was applied to acquire T1 images for each child. The results showed a bilateral reduction in grey matter volume of amygdala and hippocampus in children with ASD, but no difference was found in white matter volume. Importantly, pathological reduction in grey matter volume of amygdala was associated with lower language skills and more severe autistic traits; also, a reduced grey matter volume of the left hippocampus was related to lower language skills in the ASD group. [ABSTRACT FROM AUTHOR]

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity‐dependent changes or indirectly, by modulation of activity‐dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre‐training PL inactivation by muscimol in CREB (cAMP response element‐binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5‐s interval (CFC‐5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC‐5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC‐5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC‐5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning‐induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation. [ABSTRACT FROM AUTHOR]

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2–74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0–71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated abnormal brain overgrowth in children with autism spectrum disorder (ASD), but the development of specific brain regions, such as the amygdala and hippocampal subfields in infants, is incompletely documented. To address this issue, we performed the first MRI study of amygdala and hippocampal subfields in infants from 6 to 24 months of age using a longitudinal dataset. A novel deep learning approach, Dilated-Dense U-Net, was proposed to address the challenge of low tissue contrast and small structural size of these subfields. We performed a volume-based analysis on the segmentation results. Our results show that infants who were later diagnosed with ASD had larger left and right volumes of amygdala and hippocampal subfields than typically developing controls. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients. [ABSTRACT FROM AUTHOR]

Abnormalities in subcortical brain structures may reflect higher suicide risk in mood disorders, but less is known about its associations for schizophrenia. This cross-sectional imaging study aimed to explore whether the history of suicide attempts was associated with subcortical changes among individuals with schizophrenia. We recruited 44 individuals with schizophrenia and a history of suicide attempts (SZ-SA) and 44 individuals with schizophrenia but without a history of suicide attempts (SZ-NSA) and 44 healthy controls. Linear regression showed that SZ-SA had smaller volumes of the hippocampus (Cohen's d = −0.72), the amygdala (Cohen's d = −0.69), and some nuclei of the amygdala (Cohen's d, −0.57 to −0.72) than SZ-NSA after adjusting for age, sex, illness phase, and intracranial volume. There was no difference in the volume of the subfields of the hippocampus. It suggests the history of suicide attempts is associated with subcortical volume alterations in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)‐triggered migraine attacks. Background: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. Methods: We undertook a functional imaging study using a double‐blind placebo‐controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine‐like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty‐three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo‐continuous arterial spin labeling (3D pCASL). Results: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family‐wise error‐corrected) during NTG‐induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). Conclusions: We identified significant regional CBF changes associated with NTG‐induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment‐related heterogeneity is vital to evaluating functional imaging outcomes in migraine research. [ABSTRACT FROM AUTHOR]

Aims Alcohol use alters the reward signaling processes contributing to the development of addiction. We studied the effects of alcohol use disorder (AUD) on brain regions and blood of deceased women and men to examine sex-dependent differences in epigenetic changes associated with AUD. We investigated the effects of alcohol use on the gene promoter methylation of GABBR1 coding for GABAB receptor subunit 1 in blood and brain. Methods We chose six brain regions associated with addiction and the reward pathway (nucleus arcuatus, nucleus accumbens, the mamillary bodies, amygdala, hippocampus and anterior temporal cortex) and performed epigenetic profiling of the proximal promoter of the GABBR1 gene of post-mortem brain and blood samples of 17 individuals with AUD pathology (4 female, 13 male) and 31 healthy controls (10 female, 21 male). Results Our results show sex-specific effects of AUD on GABBR1 promoter methylation. Especially, CpG −4 showed significant tissue-independent changes and significantly decreased methylation levels for the AUD group in the amygdala and the mammillary bodies of men. We saw prominent and consistent change in CpG-4 across all investigated tissues. For women, no significant loci were observed. Conclusion We found sex-dependent differences in GABBR1 promoter methylation in relation to AUD. CpG-4 hypomethylation in male individuals with AUD is consistent for most brain regions. Blood shows similar results without reaching significance, potentially serving as a peripheral marker for addiction-associated neuronal adaptations. Further research is needed to discover more contributing factors in the pathological alterations of alcohol addiction to offer sex-specific biomarkers and treatment. [ABSTRACT FROM AUTHOR]

The amygdala, hippocampus, and subgenual cortex area 25 (A25) are engaged in complex cognitive-emotional processes. Yet pathway interactions from hippocampus and A25 with postsynaptic sites in amygdala remain largely unknown. In rhesus monkeys of both sexes, we studied with neural tracers how pathways from A25 and hippocampus interface with excitatory and inhibitory microcircuits in amygdala at multiple scales. We found that both hippocampus and A25 innervate distinct as well as overlapping sites of the basolateral (BL) amygdalar nucleus. Unique hippocampal pathways heavily innervated the intrinsic paralaminar basolateral nucleus, which is associated with plasticity. In contrast, orbital A25 preferentially innervated another intrinsic network, the intercalated masses, an inhibitory reticulum that gates amygdalar autonomic output and inhibits fear-related behaviors. Finally, using high-resolution confocal and electron microscopy (EM), we found that among inhibitory postsynaptic targets in BL, both hippocampal and A25 pathways preferentially formed synapses with calretinin (CR) neurons, which are known for disinhibition and may enhance excitatory drive in the amygdala. Among other inhibitory postsynaptic sites, A25 pathways innervated the powerful parvalbumin (PV) neurons which may flexibly regulate the gain of neuronal assemblies in the BL that affect the internal state. In contrast, hippocampal pathways innervated calbindin (CB) inhibitory neurons, which modulate specific excitatory inputs for processing context and learning correct associations. Common and unique patterns of innervation in amygdala by hippocampus and A25 have implications for how complex cognitive and emotional processes may be selectively disrupted in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co‐occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the aetiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety‐ and fear‐related behaviours. However, it is not known if this pathway influences alcohol drinking‐related behaviours. Here, we employed a rodent operant self‐administration regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g., drinking) behaviours, chemogenetics and brain region‐specific microinjections, to determine if BLA‐vHC circuitry influences alcohol and sucrose drinking‐related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety‐like behaviours on the elevated plus maze. We then demonstrated that inhibiting the BLA‐vHC pathway significantly reduced appetitive drinking‐related behaviours for both alcohol and sucrose while having no effect on consummatory measures. Taken together, these findings provide the first indication that the BLA‐vHC circuit may regulate appetitive reward seeking directed at alcohol and natural rewards and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor‐related disorders. [ABSTRACT FROM AUTHOR]

Conduct Disorder (CD) is defined as aggressive, antisocial, and rule-breaking behavior during childhood. It is a major risk factor for developing antisocial personality disorder (ASPD) in adulthood. However, nearly half the CDs do not develop ASPD. Identification of reversion factors seems crucial for proper interventions. We identified 40 subjects with childhood history of CD (CC) and 1166 control subjects (HC) from Human Connectome Project. Their psychiatric, emotional, impulsivity, and personality traits were extracted. An emotion recognition task-fMRI analysis was done. We also did subregion analysis of hippocampus and amygdala in 35 CC and 69 demographically matched HCs. CC subjects scored significantly higher in antisocial-related evaluations. No differences in task-fMRI activation of amygdala and hippocampus were observed. CCs had larger subfields of the left hippocampus: presubiculum, CA3, CA4, and dentate gyrus. Further, an interaction model revealed a significant presubiculum volume × group association with antisocial, aggression, and agreeableness scores. Our study shows that healthy young adults with a prior history of CD still exhibit some forms of antisocial-like behavior with larger left hippocampal subfields, including presubiculum that also explains the variability in antisocial behavior. These larger left hippocampal subfield volumes may play a protective role against CD to ASPD conversion. [ABSTRACT FROM AUTHOR]

Background: Based on hubs of neural circuits associated with addiction and their degree centrality (DC), this study aimed to construct the addiction-related brain networks for patients diagnosed with heroin dependence undertaking stable methadone maintenance treatment (MMT) and further prospectively identify the ones at high risk for relapse with cluster analysis. Methods: Sixty-two male MMT patients and 30 matched healthy controls (HC) underwent brain resting-state functional MRI data acquisition. The patients received 26-month follow-up for the monthly illegal-drug-use information. Ten addiction-related hubs were chosen to construct a user-defined network for the patients. Then the networks were discriminated with K-means-clustering-algorithm into different groups and followed by comparative analysis to the groups and HC. Regression analysis was used to investigate the brain regions significantly contributed to relapse. Results: Sixty MMT patients were classified into two groups according to their brain-network patterns calculated by the best clustering-number-K. The two groups had no difference in the demographic, psychological indicators and clinical information except relapse rate and total heroin consumption. The group with high-relapse had a wider range of DC changes in the cortical−striatal−thalamic circuit relative to HC and a reduced DC in the mesocorticolimbic circuit relative to the low-relapse group. DC activity in NAc, vACC, hippocampus and amygdala were closely related with relapse. Conclusion: MMT patients can be identified and classified into two subgroups with significantly different relapse rates by defining distinct brain-network patterns even if we are blind to their relapse outcomes in advance. This may provide a new strategy to optimize MMT. [ABSTRACT FROM AUTHOR]

Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its role in a chronic restraint stress (CRS) mouse model. Female and male C57Bl/6J wild-type (WT) and IL-1αβ-deficient (knock-out: IL-1 KO) mice were exposed to 6 h of immobilization/day for 4 weeks. Mechanonociception, cold tolerance, behavioral alterations, relative thymus/adrenal gland weights, microglia ionized calcium-binding adaptor molecule 1 (IBA1) and astrocyte glial fibrillary acidic protein (GFAP) integrated density, number and morphological transformation in pain-related brain regions were determined. CRS induced 15–20% mechanical hyperalgesia after 2 weeks in WT mice in both sexes, which was significantly reduced in female but not in male IL-1 KOs. Increased IBA1+ integrated density in the central nucleus of amygdala, primary somatosensory cortex hind limb representation part, hippocampus cornu ammonis area 3 (CA3) and periaqueductal gray matter (PAG) was present, accompanied by a cell number increase in IBA1+ microglia in stressed female WTs but not in IL-1 KOs. CRS induced morphological changes of GFAP+ astrocytes in WT but not in KO mice. Stress evoked cold hypersensitivity in the stressed animals. Anxiety and depression-like behaviors, thymus and adrenal gland weight changes were detectable in all groups after 2 but not 4 weeks of CRS due to adaptation. Thus, IL-1 mediates chronic stress-induced hyperalgesia in female mice, without other major behavioral alterations, suggesting the analgesic potentials of IL-1 in blocking drugs in stress-related pain syndromes. [ABSTRACT FROM AUTHOR]

Adolescence is a period of significant brain development and decreased sleep quality, making it an ideal period to investigate early indicators of anxiety disorders such as psychological distress. The amygdala and hippocampus have been implicated in the neurobiology of anxiety symptoms. Sex-based differences in anxiety symptoms and sleep quality suggest sex-specific indicators may be preferable to a "one size fits all" approach. N = 70 early adolescents (12 years) completed the Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10) and MRI scanning. Female participants were found to be poorer sleepers and to have higher psychological distress levels. Females also had larger right amygdala and hippocampal volumes than males controlling for total brain volume. Findings of sex-based differences in amygdala and hippocampal volumes as well as sleep and psychological distress at age 12 may represent an important step in elucidating sex specific early indicators of future mental health disorders. [ABSTRACT FROM AUTHOR]

Reward-seeking in the world is driven by cues that can have ambiguous predictive and motivational value. To produce adaptive, flexible reward-seeking, it is necessary to exploit occasion setters, other distinct features in the environment, to resolve the ambiguity of Pavlovian reward-paired cues. Despite this, very little research has investigated the neurobiological underpinnings of occasion setting, and as a result little is known about which brain regions are critical for occasion setting. To address this, we exploited a recently developed task that was amenable to neurobiological inquiry where a conditioned stimulus is only predictive of reward delivery if preceded in time by the non-overlapping presentation of a separate cue—an occasion setter. This task required male rats to maintain and link cue-triggered expectations across time to produce adaptive reward-seeking. We interrogated the contributions of the basolateral amygdala and orbitofrontal cortex to occasion setting as these regions are thought to be critical for the computation and exploitation of state value, respectively. Reversible inactivation of either structure prior to the occasion-setting task resulted in a profound inability of rats to use the occasion setter to guide reward-seeking. In contrast, inactivation of the dorsal hippocampus, a region fundamental for context-specific responding was without effect nor did inactivation of the basolateral amygdala or orbitofrontal cortex in a standard Pavlovian conditioning preparation affect conditioned responding. We conclude that neural activity within the orbitofrontal cortex and basolateral amygdala circuit is necessary to update and resolve ambiguity in the environment to promote cue-driven reward-seeking. [ABSTRACT FROM AUTHOR]

Social organisms synchronize behaviors as an evolutionary-conserved means of thriving. Synchronization under threat, in particular, benefits survival and occurs across species, including humans, but the underlying mechanisms remain unknown because of the scarcity of relevant animal models. Here, we developed a rodent paradigm in which mice synchronized a classically conditioned fear response and identified an underlying neuronal circuit. Male and female mice were trained individually using auditory fear conditioning and then tested 24 hours later as dyads while allowing unrestricted social interaction during exposure to the conditioned stimulus under visible or infrared illumination to eliminate visual cues. The synchronization of the immobility or freezing bouts was quantified by calculating the effect size Cohen's d for the difference between the actual freezing time overlap and the overlap by chance. The inactivation of the dorsomedial prefrontal cortex, dorsal hippocampus, or ventral hippocampus was achieved by local infusions of muscimol. The chemogenetic disconnection of the hippocampus-amygdala pathway was performed by expressing hM4D(Gi) in the ventral hippocampal neurons and infusing clozapine N -oxide in the amygdala. Mice synchronized cued but not contextual fear. It was higher in males than in females and attenuated in the absence of visible light. Inactivation of the ventral but not dorsal hippocampus or dorsomedial prefrontal cortex abolished fear synchronization. Finally, the disconnection of the hippocampus-amygdala pathway diminished fear synchronization. Mice synchronize expression of conditioned fear relying on the ventral hippocampus-amygdala pathway, suggesting that the hippocampus transmits social information to the amygdala to synchronize threat response. [ABSTRACT FROM AUTHOR]

Background: Little is known about the neural correlates of dissociative amnesia, a transdiagnostic symptom mostly present in the dissociative disorders and core characteristic of dissociative identity disorder (DID). Given the vital role of the hippocampus in memory, a prime candidate for investigation is whether total and/or subfield hippocampal volume can serve as biological markers of dissociative amnesia. Methods: A total of 75 women, 32 with DID and 43 matched healthy controls (HC), underwent structural magnetic resonance imaging (MRI). Using Freesurfer (version 6.0), volumes were extracted for bilateral global hippocampus, cornu ammonis (CA) 1–4, the granule cell molecular layer of the dentate gyrus (GC-ML-DG), fimbria, hippocampal−amygdaloid transition area (HATA), parasubiculum, presubiculum and subiculum. Analyses of covariance showed volumetric differences between DID and HC. Partial correlations exhibited relationships between the three factors of the dissociative experience scale scores (dissociative amnesia, absorption, depersonalisation/derealisation) and traumatisation measures with hippocampal global and subfield volumes. Results: Hippocampal volumes were found to be smaller in DID as compared with HC in bilateral global hippocampus and bilateral CA1, right CA4, right GC-ML-DG, and left presubiculum. Dissociative amnesia was the only dissociative symptom that correlated uniquely and significantly with reduced bilateral hippocampal CA1 subfield volumes. Regarding traumatisation, only emotional neglect correlated negatively with bilateral global hippocampus, bilateral CA1, CA4 and GC-ML-DG, and right CA3. Conclusion: We propose decreased CA1 volume as a biomarker for dissociative amnesia. We also propose that traumatisation, specifically emotional neglect, is interlinked with dissociative amnesia in having a detrimental effect on hippocampal volume. [ABSTRACT FROM AUTHOR]

Background: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. Methods: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. Results: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0–7 years) for ICV (β = −0.461, p = 0.020), TBV (β = −0.503, p = 0.021), left (β = −0.518, p = 0.020) and right hippocampi (β = −0.469, p = 0.020) and left medial orbitofrontal cortex (β = −0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. Conclusions: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population. [ABSTRACT FROM AUTHOR]

Background: Childhood trauma increases risk for psychopathology and cognitive impairment. Prior research mainly focused on the hippocampus and amygdala in single diagnostic categories. However, other brain regions may be impacted by trauma as well, and effects may be independent of diagnosis. This cross-sectional study investigated cortical and subcortical gray matter volume in relation to childhood trauma severity. Methods: We included 554 participants: 250 bipolar-I patients, 84 schizophrenia-spectrum patients and 220 healthy individuals without a psychiatric history. Participants filled in the Childhood Trauma Questionnaire. Anatomical T1 MRI scans were acquired at 3T, regional brain morphology was assessed using Freesurfer. Results: In the total sample, trauma-related gray matter reductions were found in the frontal lobe (β = −0.049, p = 0.008; q = 0.048), this effect was driven by the right medial orbitofrontal, paracentral, superior frontal regions and the left precentral region. No trauma-related volume reductions were observed in any other (sub)cortical lobes nor the hippocampus or amygdala, trauma-by-group (i.e. both patient groups and healthy subjects) interaction effects were absent. A categorical approach confirmed a pattern of more pronounced frontal gray matter reductions in individuals reporting multiple forms of trauma and across quartiles of cumulative trauma scores. Similar dose−response patterns were revealed within the bipolar and healthy subgroups, but did not reach significance in schizophrenia-spectrum patients. Conclusions: Findings show that childhood trauma is linked to frontal gray matter reductions, independent of psychiatric morbidity. Our results indicate that childhood trauma importantly contributes to the neurobiological changes commonly observed across psychiatric disorders. Frontal volume alterations may underpin affective and cognitive disturbances observed in trauma-exposed individuals. [ABSTRACT FROM AUTHOR]

Radio(chemo)therapy is used as a standard treatment for glioma patients. The surrounding normal tissue is inevitably affected by the irradiation. The aim of this longitudinal study was to investigate perfusion alterations in the normal-appearing tissue after proton irradiation and assess the dose sensitivity of the normal tissue perfusion. In 14 glioma patients, a sub-cohort of a prospective clinical trial (NCT02824731), perfusion changes in normal-appearing white matter (WM), grey matter (GM) and subcortical GM structures, i.e. caudate nucleus, hippocampus, amygdala, putamen, pallidum and thalamus, were evaluated before treatment and at three-monthly intervals after proton beam irradiation. The relative cerebral blood volume (rCBV) was assessed with dynamic susceptibility contrast MRI and analysed as the percentage ratio between follow-up and baseline image (ΔrCBV). Radiation-induced alterations were evaluated using Wilcoxon signed rank test. Dose and time correlations were investigated with univariate and multivariate linear regression models. No significant ΔrCBV changes were found in any normal-appearing WM and GM region after proton beam irradiation. A positive correlation with radiation dose was observed in the multivariate regression model applied to the combined ΔrCBV values of low (1–20 Gy), intermediate (21–40 Gy) and high (41–60 Gy) dose regions of GM (p < 0.001), while no time dependency was detected in any normal-appearing area. The perfusion in normal-appearing brain tissue remained unaltered after proton beam therapy. In further studies, a direct comparison with changes after photon therapy is recommended to confirm the different effect of proton therapy on the normal-appearing tissue. [ABSTRACT FROM AUTHOR]

ECa 233 is a standardized extract of Centella asiatica (CA), an herb widely used in traditional Chinese and Ayurvedic medicine. Previous studies reported that ECa 233 enhanced memory retention and synaptic plasticity in the hippocampus of healthy rats. Because of this, we became curious whether ECa 233 has a therapeutic effect on the fear memory deficit in the triple transgenic Alzheimer's disease (3xTg-AD) model mice. Fear memory is a crucial emotional memory for survival that is found to be impaired in patients with early-onset Alzheimer's disease (AD). In this study, we orally administered ECa 233 (doses: 10, 30, and 100 mg/kg) to 3xTg-AD mice, who were five months old, for 30 consecutive days. We found that ECa 233 prevented a cued fear memory deficit and enhanced hippocampal long-term potentiation (LTP) in 3xTg-AD mice. Subsequent proteomic and western blot analyses revealed increased expression levels of the molecules related to LTP induction and maintenance, including brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB) and its network proteins, and extracellular signal-regulated kinase 1 and 2 (ERK1 and 2) in the hippocampi and amygdala of 3xTg-AD mice after ECa 233 pre-treatment. Our results indicate that ECa 233 is a promising potential herbal standardized extract that could be used in preventing the fear memory deficit and synaptic dysfunction before the early onset of AD. [ABSTRACT FROM AUTHOR]

Background: In the fear memory network, the hippocampus modulates contextual aspects of fear learning while mutual connections between the amygdala and the medial prefrontal cortex are widely involved in fear extinction. G-protein-coupled receptors (GPCRs) are involved in the regulation of fear and anxiety, so the regulation of GPCRs in fear signaling pathways can modulate the mechanisms of fear memory acquisition, consolidation and extinction. Various studies suggested a role of M-type K+ channels in modulating fear expression and extinction, although conflicting data prevented drawing of clear conclusions. In the present work, we examined the impact of M-type K+ channel blockade or activation on contextual fear acquisition and extinction. In addition, regarding the pivotal role of the hippocampus in contextual fear conditioning (CFC) and the involvement of the axon initial segment (AIS) in neuronal plasticity, we investigated whether structural alterations of the AIS in hippocampal neurons occurred during contextual fear memory acquisition and short-time extinction in mice in a behaviorally relevant context. Results: When a single systemic injection of the M-channel blocker XE991 (2 mg/kg, IP) was carried out 15 minutes before the foot shock session, fear expression was significantly reduced. Expression of c-Fos was increased following CFC, mostly in GABAergic neurons at day 1 and day 2 post-fear training in CA1 and dentate gyrus hippocampal regions. A significantly longer AIS segment was observed in GABAergic neurons of the CA1 hippocampal region at day 2. Conclusions: Our results underscore the role of M-type K + channels in CFC and the importance of hippocampal GABAergic neurons in fear expression. [ABSTRACT FROM AUTHOR]

There may be distinct conduct disorder (CD) etiologies and neural morphologies in adolescents with high callous unemotional (CU) traits versus low CU traits. Here, we employed surface-based morphometry methods to investigate morphological differences in adolescents diagnosed with CD [42 with high CU traits (CD-HCU) and 40 with low CU traits (CD-LCU)] and healthy controls (HCs, N = 115) in China. Whole-brain analyses revealed significantly increased cortical surface area (SA) in the left inferior temporal cortex and the right precuneus, but decreased SA in the left superior temporal cortex in the CD-LCU group, compared with the HC group. There were no significant cortical SA differences between the CD-HCU and the HC groups. Compared to the CD-HCU group, the CD-LCU group had a greater cortical thickness (CT) in the left rostral middle frontal cortex. Region-of-interest analyses revealed significant group differences in the right hippocampus, with CD-HCU group having lower right hippocampal volumes than HCs. We did not detect significant group differences in the amygdalar volume, however, the right amygdalar volume was found to be a significant moderator of the correlation between CU traits and the proactive aggression in CD patients. The present results suggested that the manifestations of CD differ between those with high CU traits versus low CU traits, and underscore the importance of sample characteristics in understanding the neural substrates of CD. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) and post‐traumatic stress disorder (PTSD) are highly comorbid, yet there is a lack of preclinical research investigating how prior ethanol (EtOH) dependence influences the development of a PTSD‐like phenotype. Furthermore, the neuroimmune system has been implicated in the development of both AUD and PTSD, but the extent of glial involvement in this context remains unclear. A rodent model was developed to address this gap in the literature. Methods: We used a 15‐day exposure to the 5% w/v EtOH low‐fat Lieber‐DeCarli liquid diet in combination with the stress‐enhanced fear learning (SEFL) paradigm to investigate the effects of chronic EtOH consumption on the development of a PTSD‐like phenotype. Next, we used a reverse transcription quantitative real‐time polymerase chain reaction to quantify mRNA expression of glial cell markers GFAP (astrocytes) and CD68 (microglia) following severe footshock stress in EtOH‐withdrawn rats. Finally, we tested the functional contribution of dorsal hippocampal (DH) astrocytes in the development of SEFL in EtOH‐dependent rats using astrocyte‐specific Gi designer receptors exclusively activated by designer drugs (Gi‐DREADD). Results: Results demonstrate that chronic EtOH consumption and withdrawal exacerbate future SEFL. Additionally, we found significantly increased GFAP mRNA expression in the dorsal and ventral hippocampus and amygdalar complex following the severe stressor in EtOH‐withdrawn animals. Finally, the stimulation of the astroglial Gi‐DREADD during EtOH withdrawal prevented the EtOH‐induced enhancement of SEFL. Conclusions: Collectively, results indicate that prior EtOH dependence and withdrawal combined with a severe stressor potentiate future enhanced fear learning. Furthermore, DH astrocytes significantly contribute to this change in behavior. Overall, these studies provide insight into the comorbidity of AUD and PTSD and the potential neurobiological mechanisms behind increased susceptibility to a PTSD‐like phenotype in individuals with AUD. [ABSTRACT FROM AUTHOR]

Early life stress (ELS) can cause long-term changes in gene expression, affect cognition, mood, and behavior, and increase susceptibility to post-traumatic stress disorder (PTSD) in adulthood, in which the histone acetylation plays a crucial role. Studies have found that environmental enrichment (EE) mitigated the unfavorable outcomes of ELS. However, the underlying mechanism of the histone acetylation is not yet completely clear. The purpose of this study was to explore the effect of EE on the histone acetylation after ELS. In this study, using single prolonged stress (SPS) paradigm in early adolescent rats explored the long-term effects of ELS on behavior, the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), as well as the acetylation levels of the lysine 9 site of histone H3 (H3K9) and lysine 12 site of histone H4 (H4K12) in the hippocampus and amygdala. Meanwhile, the protective effects of EE intervention were examined. We found that adult male rats exposed to ELS showed behavioral changes, including reduced locomotor activity, increased anxiety-like behaviors, impaired spatial learning and memory, enhanced contextual and cued fear memory, and the HATs/HDACs ratio and acetyl H3K9 (Ac–H3K9) and acetyl H4K12 (Ac–H4K12) were increased in the hippocampus and decreased in the amygdala. Furthermore, EE attenuated the behavioral abnormalities from ELS, possibly through down-regulating the activity of HATs in the hippocampus and up-regulating HDACs activities in the amygdala. These finding suggested that EE could ameliorate ELS-induced PTSD-like behaviors by regulating histone acetylation in the hippocampus and amygdala, reducing the susceptibility to PTSD in adulthood. [ABSTRACT FROM AUTHOR]

Background: The goal of the brain is to provide right on time a suitable earlier-acquired model for the future behavior. How a complex structure of neuronal activity underlying a suitable model is selected or fixated is not well understood. Here we propose the integrated information Φ as a possible metric for such complexity of neuronal groups. It quantifies the degree of information integration between different parts of the brain and is lowered when there is a lack of connectivity between different subsets in a system. Methods: We calculated integrated information coefficient (Φ) for activity of hippocampal and amygdala neurons in rats during acquisition of two tasks: spatial task followed by spatial aversive task. An Autoregressive Φ algorithm was used for time-series spike data. Results: We showed that integrated information coefficient Φ is positively correlated with a metric of learning success (a relative number of rewards). Φ for hippocampal neurons was positively correlated with Φ for amygdalar neurons during the learning requiring the cooperative work of hippocampus and amygdala. Conclusions: This result suggests that integrated information coefficient Φ may be used as a prediction tool for the suitable level of complexity of neuronal activity and the future success in learning and adaptation and a tool for estimation of interactions between different brain regions during learning. [ABSTRACT FROM AUTHOR]