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There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT 2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT 2A receptors. Restoration of 5-HT 2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT 2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior. [Display omitted] • The psychedelic DOI evokes acute anxiolytic effects in rodent models via the vHpc • DOI enhances the firing rate of a fast-spiking neuron subpopulation in the vHpc • Opto-tagging reveals that DOI recruits PV-positive inhibitory interneurons in the vHpc • Agonism of 5-HT 2A receptors on PV neurons in the vHpc mediate evoked anxiolysis Tiwari et al. identify the discrete neural circuit underlying the acute anxiolytic actions of the serotonergic psychedelic DOI, demonstrating that DOI recruits 5-HT 2A receptors on parvalbumin-positive, fast-spiking inhibitory interneurons in the ventral hippocampal CA1/subiculum region to drive its acute anxiolytic effects. [ABSTRACT FROM AUTHOR]

Background: This study investigated for a possible contributing role of hippocampus in the different clinical phenotypic manifestations of migraine aura. Methods: Herein, patients were categorized as those with pure visual aura (MwAv), those who reported additional somatosensory and dysphasic symptoms (MwAvsd), and healthy controls (HCs). Neuroimaging data obtained using FreeSurfer-based segmentation of hippocampal subfields were compared between HCs and patients with migraine with aura, as well as between HCs and those with MwAv and MwAvsd. The average migraine aura complexity score (MACS) was calculated for each patient to investigate the correlation between hippocampal subfield volume and migraine aura complexity. Results: Herein, 46 patients with migraine with aura (28 MwAvsd and 18 MwAv) and 31 HCs were included. There were no significant differences in the hippocampal subfields between HCs and patients with migraine with aura. The average MACS negatively correlated with the volumes of the left and right hippocampi, Cornu Ammonis (CA) 1, CA3, CA4, molecular layer, left granule cell layer of the dentate gyrus, hippocampal fissure, and hippocampus-amygdala transition area. The MwAvsd subgroup had significantly smaller whole hippocampal volumes in both hemispheres, as well as in both subicula, compared with the MwAv subgroup and HCs. In addition, the left molecular layer, right CA1, and hippocampal fissures were significantly smaller in the MwAvsd group than in the MwAv subgroup and HCs. Conclusions: Smaller left and right hippocampal volumes, particularly of the subiculum/CA1 area, may play an important role in the pathophysiology of somatosensory and dysphasic symptoms in migraine with aura. [ABSTRACT FROM AUTHOR]

Summary: The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non‐rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep–wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep–wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second‐order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep–wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep‐deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness. [ABSTRACT FROM AUTHOR]

Abstract Background This study investigated for a possible contributing role of hippocampus in the different clinical phenotypic manifestations of migraine aura. Methods Herein, patients were categorized as those with pure visual aura (MwAv), those who reported additional somatosensory and dysphasic symptoms (MwAvsd), and healthy controls (HCs). Neuroimaging data obtained using FreeSurfer-based segmentation of hippocampal subfields were compared between HCs and patients with migraine with aura, as well as between HCs and those with MwAv and MwAvsd. The average migraine aura complexity score (MACS) was calculated for each patient to investigate the correlation between hippocampal subfield volume and migraine aura complexity. Results Herein, 46 patients with migraine with aura (28 MwAvsd and 18 MwAv) and 31 HCs were included. There were no significant differences in the hippocampal subfields between HCs and patients with migraine with aura. The average MACS negatively correlated with the volumes of the left and right hippocampi, Cornu Ammonis (CA) 1, CA3, CA4, molecular layer, left granule cell layer of the dentate gyrus, hippocampal fissure, and hippocampus-amygdala transition area. The MwAvsd subgroup had significantly smaller whole hippocampal volumes in both hemispheres, as well as in both subicula, compared with the MwAv subgroup and HCs. In addition, the left molecular layer, right CA1, and hippocampal fissures were significantly smaller in the MwAvsd group than in the MwAv subgroup and HCs. Conclusions Smaller left and right hippocampal volumes, particularly of the subiculum/CA1 area, may play an important role in the pathophysiology of somatosensory and dysphasic symptoms in migraine with aura.

Hippocampal CA3 is traditionally conceptualized as a brain region within a unidirectional feedforward trisynaptic pathway that links major hippocampal subregions. Recent genomic and viral tracing studies indicate that the anatomical connectivity of CA3 and the trisynaptic pathway is more complex than initially expected and suggests that there may be cell type-specific input gradients throughout the three-dimensional hippocampal structure. In several recent studies using multiple viral tracing approaches, we describe subdivisions of the subiculum complex and ventral hippocampal CA1 that show significant back projections to CA1 and CA3 excitatory neurons. These novel connections form noncanonical circuits that run in the opposite direction relative to the well-characterized feedforward pathway. Diverse subtypes of GABAergic inhibitory neurons participate within the trisynaptic pathway. In the present study, we have applied monosynaptic retrograde viral tracing to examine noncanonical synaptic inputs from CA1 and subicular complex to the inhibitory neuron in hippocampal CA3. We quantitatively mapped synaptic inputs to CA3 inhibitory neurons to understand how they are connected within and beyond the hippocampus formation. Major brain regions that provide typical inputs to CA3 inhibitory neurons include the medial septum, the dentate gyrus, the entorhinal cortex, and CA3. Noncanonical inputs from ventral CA1 and subicular complex to CA3 inhibitory neurons follow a proximodistal topographic gradient with regard to CA3 subregions. We find novel noncanonical circuit connections between inhibitory CA3 neurons and ventral CA1, subiculum complex, and other brain regions. These results provide a new anatomical connectivity basis to further study the function of CA3 inhibitory neurons.

The balance between excitation and inhibition is essential to the proper function of cortical circuits. To maintain this balance during dynamic network activity, modulation of the strength of inhibitory synapses is a central requirement. In this study, we aimed to characterize perisomatic inhibition and its plasticity onto pyramidal cells (PCs) in the subiculum, the main output region of the hippocampus. We performed whole-cell patch-clamp recordings from the two main functional PC types, burst (BS) and regular spiking (RS) neurons in acute rat hippocampal slices and applied two different extracellular high-frequency stimulation paradigms: non-associative (presynaptic stimulation only) and associative stimulation (concurrent pre-and postsynaptic stimulation) to induce plasticity. Our results revealed cell type-specific differences in the expression of inhibitory plasticity depending on the induction paradigm: While associative stimulation caused robust inhibitory plasticity in both cell types, non-associative stimulation produced long-term potentiation in RS, but not in BS PCs. Analysis of paired-pulse ratio, variance of IPSPs, and postsynaptic Ca2+ buffering indicated a dominant postsynaptic calcium-dependent signaling and expression of inhibitory plasticity in both PC types. This divergence in inhibitory plasticity complements a stronger inhibition and a higher intrinsic excitability in RS as compared to BS neurons, suggesting differential involvement of the two PC types during network activation and information processing in the subiculum. [ABSTRACT FROM AUTHOR]

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance. [ABSTRACT FROM AUTHOR]

The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning andmemory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD. [ABSTRACT FROM AUTHOR]

Developmental topographical disorientation (DTD) refers to the lifelong inability to orient by means of cognitive maps in familiar surroundings despite otherwise well‐preserved general cognitive functions, and the absence of any acquired brain injury or neurological condition. While reduced functional connectivity between the hippocampus and other brain regions has been reported in DTD individuals, no structural differences in gray matter tissue for the whole brain neither for the hippocampus were detected. Considering that the human hippocampus is the main structure associated with cognitive map‐based navigation, here, we investigated differences in morphological and morphometric hippocampal features between individuals affected by DTD (N = 20) and healthy controls (N = 238). Specifically, we focused on a developmental anomaly of the hippocampus that is characterized by the incomplete infolding of hippocampal subfields during fetal development, giving the hippocampus a more round or pyramidal shape, called incomplete hippocampal inversion (IHI). We rated IHI according to standard criteria and extracted hippocampal subfield volumes after FreeSurfer's automatic segmentation. We observed similar IHI prevalence in the group of individuals with DTD with respect to the control population. Neither differences in whole hippocampal nor major hippocampal subfield volumes have been observed between groups. However, when assessing the IHI independent criteria, we observed that the hippocampus in the DTD group is more medially positioned comparing to the control group. In addition, we observed bigger hippocampal fissure volume for the DTD comparing to the control group. Both of these findings were stronger for the right hippocampus comparing to the left. Our results provide new insights regarding the hippocampal morphology of individuals affected by DTD, highlighting the role of structural anomalies during early prenatal development in line with the developmental nature of the spatial disorientation deficit. [ABSTRACT FROM AUTHOR]

Background: The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer's disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage. Objective: Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD. Methods: Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau). Results: We found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice. Conclusions: These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions. [ABSTRACT FROM AUTHOR]

The hippocampal subfield prosubiculum (ProS), is a conserved neuroanatomic region in mouse, monkey, and human. This area lies between CA1 and subiculum (Sub) and particularly lacks consensus on its boundaries; reports have varied on the description of its features and location. In this report, we review, refine, and evaluate four cytoarchitectural features that differentiate ProS from its neighboring subfields: (1) small neurons, (2) lightly stained neurons, (3) superficial clustered neurons, and (4) a cell sparse zone. ProS was delineated in all cases (n = 10). ProS was examined for its cytoarchitectonic features and location rostrocaudally, from the anterior head through the body in the hippocampus. The most common feature was small pyramidal neurons, which were intermingled with larger pyramidal neurons in ProS. We quantitatively measured ProS pyramidal neurons, which showed (average, width at pyramidal base = 14.31 µm, n = 400 per subfield). CA1 neurons averaged 15.57 µm and Sub neurons averaged 15.63 µm, both were significantly different than ProS (Kruskal–Wallis test, p <.0001). The other three features observed were lightly stained neurons, clustered neurons, and a cell sparse zone. Taken together, these findings suggest that ProS is an independent subfield, likely with distinct functional contributions to the broader interconnected hippocampal network. Our results suggest that ProS is a cytoarchitecturally varied subfield, both for features and among individuals. This diverse architecture in features and individuals for ProS could explain the long‐standing complexity regarding the identification of this subfield. [ABSTRACT FROM AUTHOR]

Summary: The mammillary bodies (MBOs), a group of hypothalamic nuclei, play a pivotal role in memory formation and spatial navigation. They receive extensive inputs from the hippocampus through the fornix, but the physiological significance of these connections remains poorly understood. Damage to the MBOs is associated with various forms of anterograde amnesia. However, information about the physiological characteristics of the MBO is limited, primarily due to the limited number of studies that have directly monitored MBO activity along with population patterns of its upstream partners. Employing large-scale silicon probe recording in mice, we characterize MBO activity and its interaction with the subiculum across various brain states. We find that MBO cells are highly diverse in their relationship to theta, ripple, and slow oscillations. Several of the physiological features are inherited by the topographically organized inputs to MBO cells. Our study provides insights into the functional organization of the MBOs.

Subiculum is a pivotal output component of the hippocampal formation, a structure often overlooked in neuroscientific research. Here, this review aims to explore the role of the subiculum in various brain disorders, shedding light on its significance within the functional-neuroanatomical perspective on neurological diseases. The subiculum's involvement in multiple brain disorders was thoroughly examined. In Alzheimer's disease, subiculum alterations precede cognitive decline, while in epilepsy, the subiculum plays a critical role in seizure initiation. Stress involves the subiculum's impact on the hypothalamic-pituitary-adrenocortical axis. Moreover, the subiculum exhibits structural and functional changes in anxiety, schizophrenia, and Parkinson's disease, contributing to cognitive deficits. Bipolar disorder is linked to subiculum structural abnormalities, while autism spectrum disorder reveals an alteration of inward deformation in the subiculum. Lastly, frontotemporal dementia shows volumetric differences in the subiculum, emphasizing its contribution to the disorder's complexity. Taken together, this review consolidates existing knowledge on the subiculum's role in brain disorders, and may facilitate future research, diagnostic strategies, and therapeutic interventions for various neurological conditions.

The bed nucleus of stria terminalis (BST) is a critical structure that mediates sustained vigilant responses to contextual, diffuse, and unpredictable threats. Dysfunction of the BST could lead to excessive anxiety and hypervigilance, which are often observed in posttraumatic stress disorder and anxiety disorders. Vigilance of potential future threats from the external environment is a basic brain function and probably requires rapid and/or short neural circuits, which enable both quick detection of the potential threats and fast adaptive responses. However, the BST in literature does not appear to receive spatial information directly from earlier visual or spatial processing structures. In this study, a novel subdivision of the BST is uncovered in monkey, rat, and mouse brains based on the human equivalent and is found in mouse to receive direct inputs from the ventral lateral geniculate nucleus and pretectal nucleus as well as from the spatial processing structures such as subiculum, presubiculum, and medial entorhinal cortex. This new subdivision, termed spindle‐shaped small cell subdivision (BSTsc), is located between the known BST and the anterior thalamus. In addition to the unique afferent connections and cell morphology, the BSTsc also displays unique molecular signature (e.g., positive for excitatory markers) compared with other BST subdivisions, which are mostly composed of inhibitory GABAergic neurons. The BSTsc appears to have largely overlapping efferent projections with other BST subdivisions such as the projections to the amygdala, hypothalamus, nucleus accumbens, septum, and brainstem. Together, the present study suggests that the BSTsc is poised to serve as a shortcut bridge directly linking spatial information from the environment to vigilant adaptive internal responses. [ABSTRACT FROM AUTHOR]

The balance between excitation and inhibition is essential to the proper function of cortical circuits. To maintain this balance during dynamic network activity, modulation of the strength of inhibitory synapses is a central requirement. In this study, we aimed to characterize perisomatic inhibition and its plasticity onto pyramidal cells (PCs) in the subiculum, the main output region of the hippocampus. We performed whole-cell patch-clamp recordings from the two main functional PC types, burst (BS) and regular spiking (RS) neurons in acute rat hippocampal slices and applied two different extracellular high-frequency stimulation paradigms: non-associative (presynaptic stimulation only) and associative stimulation (concurrent pre-and postsynaptic stimulation) to induce plasticity. Our results revealed cell type-specific differences in the expression of inhibitory plasticity depending on the induction paradigm: While associative stimulation caused robust inhibitory plasticity in both cell types, non-associative stimulation produced long-term potentiation in RS, but not in BS PCs. Analysis of paired-pulse ratio, variance of IPSPs, and postsynaptic Ca2+ buffering indicated a dominant postsynaptic calcium-dependent signaling and expression of inhibitory plasticity in both PC types. This divergence in inhibitory plasticity complements a stronger inhibition and a higher intrinsic excitability in RS as compared to BS neurons, suggesting differential involvement of the two PC types during network activation and information processing in the subiculum.

Background: Adverse Childhood Experience (ACE) has detrimental impacts on neural development, especially hippocampal morphometry. Mindfulness-Based Interventions (MBI) has been shown to induce adaptive hippocampal changes especially at the subiculum. The present study aims to investigate the effects of MBI on subiculum volumes among ACE survivors, as well as the effects on episodic memory as a probe into hippocampal functionality. Methods: We analyzed anatomical MRI data and performance indices from an episodic memory task called the Mnemonic Similarity Task (MST) collected from a randomized controlled longitudinal study that compared an 8-week MBI (N = 20) to an active control condition of Stress Management Education (SME) (N = 19). FreeSurfer 6.0 was used for automated hippocampal subfield segmentation and volumetric estimation. Results: Significant group differences were observed with the volumetric changes of the right whole hippocampus and right subiculum. Only the MBI group showed improved pattern separation capability from MST, which was associated with stress reduction and right subiculum volumetric changes. Limitations: Modest sample size. MST task was performed outside of MRI. Conclusions: These findings suggest beneficial effects of MBI for hippocampal volumes and episodic memory, while highlighting the importance of the subiculum for MBI-induced neural and cognitive changes. The subiculum's known role in inhibitory control was interpreted as a potential mechanism for it to exhibit MBI-induced volumetric changes, which sheds light on the potential neural underpinnings of mindfulness meditation for reducing stress reactivity among ACE survivors.

Dementia is often characterized by age-dependent cerebrovascular pathology, neuroinflammation, and cognitive deficits with notable sex differences in risk, disease onset, progression and severity. Women bear a disproportionate burden of dementia, and the onset of menopause (i.e., perimenopause) may be a critical period conferring increased susceptibility. However, the contribution of early ovarian decline to the neuroinflammatory processes associated with cerebrovascular dementia risks, particularly at the initial stages of pathology that may be more amenable to proactive intervention, is unknown. To better understand the influence of early ovarian failure on dementia-associated neuroinflammation we developed a model of perimenopausal cerebral amyloid angiopathy (CAA), an important contributor to dementia. For this, accelerated ovarian failure (AOF) was induced by 4-vinylcyclohexene diepoxide (VCD) treatment to isolate early-stage ovarian failure comparable to human perimenopause (termed "peri-AOF") in transgenic SWDI mice expressing human vasculotropic mutant amyloid beta (Aβ) precursor protein, that were also tested at an early stage of amyloidosis. We found that peri-AOF SWDI mice showed increased astrocyte activation accompanied by elevated Aβ in select regions of the hippocampus, a brain system involved in learning and memory that is severely impacted during dementia. However, although SWDI mice showed signs of increased hippocampal microglial activation and impaired cognitive function, this was not further affected by peri-AOF. In sum, these results suggest that elevated dysfunction of key elements of the neurovascular unit in select hippocampal regions characterizes the brain pathology of mice at early stages of both CAA and AOF. However, neurovascular unit pathology may not yet have passed a threshold that leads to further behavioral compromise at these early periods of cerebral amyloidosis and ovarian failure. These results are consistent with the hypothesis that the hormonal dysregulation associated with perimenopause onset represents a stage of emerging vulnerability to dementia- associated neuropathology, thus providing a selective window of opportunity for therapeutic intervention prior to the development of advanced pathology that has proven difficult to repair or reverse. [ABSTRACT FROM AUTHOR]

Objective: To investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP). Methods: 50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance. Results: The volume of the left subicular complex was highly correlated to learning performance (ß = 0.284; p = 0.042) and free recall performance in the VLMT (ß = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (ß = 0.378; p = 0.006) and recognition performance in the VLMT (ß = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance. Conclusion: The results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance. [ABSTRACT FROM AUTHOR]

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two‐step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between‐rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross‐validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within‐rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas. [ABSTRACT FROM AUTHOR]

IntroductionHippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)-detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP).MethodsQuery of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS-/ADNP+) and without (HS-/ADNP-).ResultsHS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; left P

Dementia is often characterized by age-dependent cerebrovascular pathology, neuroinflammation, and cognitive deficits with notable sex differences in risk, disease onset, progression and severity. Women bear a disproportionate burden of dementia, and the onset of menopause (i.e., perimenopause) may be a critical period conferring increased susceptibility. However, the contribution of early ovarian decline to the neuroinflammatory processes associated with cerebrovascular dementia risks, particularly at the initial stages of pathology that may be more amenable to proactive intervention, is unknown. To better understand the influence of early ovarian failure on dementia-associated neuroinflammation we developed a model of perimenopausal cerebral amyloid angiopathy (CAA), an important contributor to dementia. For this, accelerated ovarian failure (AOF) was induced by 4-vinylcyclohexene diepoxide (VCD) treatment to isolate early-stage ovarian failure comparable to human perimenopause (termed “peri-AOF”) in transgenic SWDI mice expressing human vasculotropic mutant amyloid beta (Aβ) precursor protein, that were also tested at an early stage of amyloidosis. We found that peri-AOF SWDI mice showed increased astrocyte activation accompanied by elevated Aβ in select regions of the hippocampus, a brain system involved in learning and memory that is severely impacted during dementia. However, although SWDI mice showed signs of increased hippocampal microglial activation and impaired cognitive function, this was not further affected by peri-AOF. In sum, these results suggest that elevated dysfunction of key elements of the neurovascular unit in select hippocampal regions characterizes the brain pathology of mice at early stages of both CAA and AOF. However, neurovascular unit pathology may not yet have passed a threshold that leads to further behavioral compromise at these early periods of cerebral amyloidosis and ovarian failure. These results are consistent with the hypothesis that the hormonal dysregulation associated with perimenopause onset represents a stage of emerging vulnerability to dementia-associated neuropathology, thus providing a selective window of opportunity for therapeutic intervention prior to the development of advanced pathology that has proven difficult to repair or reverse.

ObjectiveTo investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP).Methods50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance.ResultsThe volume of the left subicular complex was highly correlated to learning performance (β = 0.284; p = 0.042) and free recall performance in the VLMT (β = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (β = 0.378; p = 0.006) and recognition performance in the VLMT (β = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance.ConclusionThe results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

Glutamate is the main excitatory neurotransmitter in the central nervous system, responsible for a plethora of cellular processes including memory formation and higher cerebral function and has been implicated in various neurological disease states. Alzheimer’s disease (AD) is the leading neurodegenerative disorder worldwide and is characterized by significant cell loss and glutamatergic dysfunction. While there has been a focus on ionotropic glutamatergic receptors few studies have attempted to elucidate the pathological changes of metabotropic glutamate receptors (mGluRs) in AD. mGluRs are G-protein coupled receptors which have a wide-ranging functionality, including the regulation of neuronal injury and survival. In particular, the group I mGluRs (mGluR1 and mGluR5) are associated with ionotropic receptor activation and upregulation with resultant glutamate release in normal neuronal functioning. The mGluR subtype 1 splice variant a (mGluR1α) is the longest variant of the mGluR1 receptor, is localized to dendritic processes and is mainly plasma membrane-bound. Activation of mGluR1a has been shown to result in increased constitutive activity of ionotropic receptors, although its role in neurodegenerative and other neurological diseases is controversial, with some animal studies demonstrating potential neuroprotective properties in excito- and neurotoxic environments. In this study, the expression of mGluR1a within normal and AD human hippocampal tissue was quantified using immunohistochemistry. We found a significantly reduced expression of mGluR1α within the stratum pyramidale and radiatum of the CA1subregion, subiculum, and entorhinal cortex. This downregulation could result in potential dysregulation of the glutamatergic system with consequences on AD progression by promoting excitotoxicity, but alternatively may also be a neuroprotective mechanism to prevent mGluR1α associated excitotoxic effects. In summary, more research is required to understand the role and possible consequences of mGluR1α downregulation in the human AD hippocampus, subiculum and entorhinal cortex and its potential as a therapeutic target.

In neonatal brain development there is a period of normal apoptotic cell death that regulates adult neuron number. At approximately the same period, ethanol exposure can cause a dramatic spike in apoptotic cell death. While ethanol-induced apoptosis has been shown to reduce adult neuron number, questions remain about the regional selectivity of the ethanol effect, and whether the brain might have some capacity to overcome the initial neuron loss. The present study used stereological cell counting to compare cumulative neuron loss 8 h after postnatal day 7 (P7) ethanol treatment to that of animals left to mature to adulthood (P70). Across several brain regions we found that the reduction of total neuron number after 8 h was as large as that of adult animals. Comparison between regions revealed that some areas are more vulnerable, with neuron loss in the anterior thalamic nuclei > the medial septum/vertical diagonal band, dorsal subiculum, and dorsal lateral geniculate nucleus > the mammillary bodies and cingulate cortex > whole neocortex. In contrast to estimates of total neuron number, estimates of apoptotic cell number in Nissl-stained sections at 8 h after ethanol treatment provided a less reliable predictor of adult neuron loss. The findings show that ethanol-induced neonatal apoptosis often causes immediate neuron deficits that persist in adulthood, and furthermore suggests that the brain may have limited capacity to compensate for ethanol-induced neuron loss. [ABSTRACT FROM AUTHOR]

Malfunction of the ventral subiculum (vSub), the main subregion controlling the output connections from the hippocampus, is associated with major depressive disorder (MDD). Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca (MSDB), whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive. Here, we found that chronic unpredictable mild stress (CUMS) induced depression-like behaviors with hyperactivation of vSub neurons, measured by c-fos staining and whole-cell patch-clamp recording. By retrograde and anterograde tracing, we confirmed the dense MSDB cholinergic innervation of the vSub. In addition, transient restraint stress in CUMS increased the level of ACh in the vSub. Furthermore, chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors; and local infusion of atropine, a muscarinic receptor antagonist, into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS. Together, these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors, revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression. [ABSTRACT FROM AUTHOR]

In neonatal brain development there is a period of normal apoptotic cell death that regulates adult neuron number. At approximately the same period, ethanol exposure can cause a dramatic spike in apoptotic cell death. While ethanol-induced apoptosis has been shown to reduce adult neuron number, questions remain about the regional selectivity of the ethanol effect, and whether the brain might have some capacity to overcome the initial neuron loss. The present study used stereological cell counting to compare cumulative neuron loss 8 h after postnatal day 7 (P7) ethanol treatment to that of animals left to mature to adulthood (P70). Across several brain regions we found that the reduction of total neuron number after 8 h was as large as that of adult animals. Comparison between regions revealed that some areas are more vulnerable, with neuron loss in the anterior thalamic nuclei > the medial septum/vertical diagonal band, dorsal subiculum, and dorsal lateral geniculate nucleus > the mammillary bodies and cingulate cortex > whole neocortex. In contrast to estimates of total neuron number, estimates of apoptotic cell number in Nissl-stained sections at 8 h after ethanol treatment provided a less reliable predictor of adult neuron loss. The findings show that ethanol-induced neonatal apoptosis often causes immediate neuron deficits that persist in adulthood, and furthermore suggests that the brain may have limited capacity to compensate for ethanol-induced neuron loss.

Introduction: The hippocampus is integral for learning and memory and is targeted by multiple diseases. Neuroimaging approaches frequently use hippocampal subfield volumes as a standard measure of neurodegeneration, thus making them an essential biomarker to study. Collectively, histologic parcellation studies contain various disagreements, discrepancies, and omissions. The present study aimed to advance the hippocampal subfield segmentation field by establishing the first histology based parcellation protocol, applied to n = 22 human hippocampal samples. Methods: The protocol focuses on five cellular traits observed in the pyramidal layer of the human hippocampus. We coin this approach the pentad protocol. The traits were: chromophilia, neuron size, packing density, clustering, and collinearity. Subfields included were CA1, CA2, CA3, CA4, prosubiculum, subiculum, presubiculum, parasubiculum, as well as the medial (uncal) subfields Subu, CA1u, CA2u, CA3u, and CA4u. We also establish nine distinct anterior-posterior levels of the hippocampus in the coronal plane to document rostrocaudal differences. Results: Applying the pentad protocol, we parcellated 13 subfields at nine levels in 22 samples. We found that CA1 had the smallest neurons, CA2 showed high neuronal clustering, and CA3 displayed the most collinear neurons of the CA fields. The border between presubiculum and subiculum was staircase shaped, and parasubiculum had larger neurons than presubiculum. We also demonstrate cytoarchitectural evidence that CA4 and prosubiculum exist as individual subfields. Discussion: This protocol is comprehensive, regimented and supplies a high number of samples, hippocampal subfields, and anterior-posterior coronal levels. The pentad protocol utilizes the gold standard approach for the human hippocampus subfield parcellation. [ABSTRACT FROM AUTHOR]

Abstract Background The hippocampus has for long been known for its ability to form new, declarative memory. However, emerging findings across conditions in the psychosis spectrum also implicate its role in emotional regulation. Systematic reviews have demonstrated consistent volume atrophic changes in the hippocampus. The aim of the systematic review and metanalysis which will follow from this protocol will be to investigate the volume-based neuroimaging findings across each of the subfields of the hippocampus in psychosis independent of diagnosis. Methods Volume changes across subfields of the hippocampus in psychotic illnesses will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MRI neuroimaging studies of patients with a definitive diagnosis of psychosis (including brief pre-diagnostic states) will be included. Studies lacking adequate controls, illicit drug use, medical psychosis, history of other significant psychiatric comorbidities, or emphasis on age groups above 65 or below 16 will be excluded. Subfields investigated will include the CA1, CA2/3, CA4, subiculum, presubiculum, parasubiculum, dentate gyrus, stratum, molecular layer, granular cell layer, entorhinal cortex, and fimbria. Two people will independently screen abstracts from the output of the search to select suitable studies. This will be followed by the two reviewers performing a full-text review of the studies which were selected based on suitable abstracts. One reviewer will independently perform all the data extraction, and another reviewer will then systemically check all the extracted information using the original articles to ensure accuracy. Statistical analysis will be performed using the metafor and meta-packages in R Studio with the application of the random-effects model. Discussion This study will provide insight into the volumetric changes in psychosis of the subfields of the hippocampus, independent of diagnosis. This may shed light on the intricate neural pathology which encompasses psychosis and will open avenues for further exploration of the structures identified as potential drivers of volume change. Systematic review registration PROSPERO CRD42020199558

Summary: Sharp wave-ripples (SWRs) are hippocampal oscillations associated with memory consolidation. The subiculum, as the hippocampal output structure, ensures that hippocampal memory representations are transferred correctly to the consolidating neocortical regions. Because patients with temporal lobe epilepsy often develop memory deficits, we hypothesized that epileptic networks may disrupt subicular SWRs. We therefore investigated the impact of experimentally induced status epilepticus (SE) on subicular SWRs and contributing pyramidal neurons using electrophysiological recordings in mouse hippocampal slices. Subicular SWRs expressed hyperexcitable features post-SE, including increased ripple and unit activity. While regular firing neurons normally remain silent during SWRs, selective disinhibition recruited more regular firing neurons for action potential generation during SWRs post-SE. By contrast, burster neurons generated fewer action potential bursts during SWRs post-SE. Furthermore, altered timing of postsynaptic and action potentials suggested distorted neuronal recruitment during SWRs. Distorted subicular SWRs may therefore impair information processing and memory consolidation in epilepsy.

Epileptic seizures result in pronounced over-expression of neuropeptide Y (NPY). In vivo and in vitro studies revealed that NPY exerts potent anticonvulsive actions through presynaptic Y2 receptors by suppressing glutamate release from principal neurons. We now investigated whether seizure-induced over-expression of NPY contributes to epileptic tolerance induced by preceding seizures. We used a previously established animal model based on selective inhibition of GABA release from parvalbumin (PV)-containing interneurons in the subiculum in mice. The animals present spontaneous recurrent seizures (SRS) and clusters of interictal spikes (IS). The frequency of SRS declined after five to six weeks, indicating development of seizure tolerance. In interneurons of the subiculum and sector CA1, SRS induced over-expression of NPY that persisted there for a prolonged time despite of a later decrease in SRS frequency. In contrast to NPY, somatostatin was not overexpressed in the respective axon terminals. Contrary to interneurons, NPY was only transiently expressed in mossy fibers. To demonstrate a protective function of endogenous, over-expressed NPY, we injected the selective NPY-Y2 receptor antagonist JNJ 5207787 simultaneously challenging the mice by a low dose of pentylenetetrazol (PTZ, 30 or 40 mg/kg, i.p.). In control mice, neither PTZ nor PTZ plus JNJ 5207787 induced convulsions. In mice with silenced GABA/PV neurons, PTZ alone only modestly enhanced EEG activity. When we injected JNJ 5207787 together with PTZ (either dose) the number of seizures, however, became significantly increased. In addition, in the epileptic mice CB1 receptor immunoreactivity was reduced in terminal areas of basket cells pointing to reduced presynaptic inhibition of GABA release from these neurons. Our experiments demonstrate that SRS result in overexpression of NPY in hippocampal interneurons. NPY overexpression persists for several weeks and may be related to later decreasing SRS frequency. Injection of the Y2 receptor antagonist JNJ 5207787 prevents this protective action of NPY only when release of the peptide is triggered by injection of PTZ and induces pronounced convulsions. Thus, over-expressed NPY released "on demand" by seizures may help terminating acute seizures and may prevent from recurrent epileptic activity. [ABSTRACT FROM AUTHOR]

Background Evidence suggests that select hippocampal subfields are implicated in the initial stages of Alzheimer's disease (AD) and are selectively involved in objective memory. Less is known whether subfields are associated with informant-reported memory difficulties of individuals with a diagnosis of mild cognitive impairment (MCI). Method Data from 56 participants with a diagnosis of amnestic MCI were included in the present study. To test whether FreeSurfer derived hippocampal subfields (CA1–4, subiculum, presubiculum, and dentate gyrus) were associated with objective (learning and delayed recall) and informant-reports of memory difficulties, we used multiple linear regression analysis. Subfields were adjusted for total intracranial volume, and age, sex, and years of education were included as covariates in all models. Results Larger presubiculum, subiculum, and CA4/dentate gyrus volumes were associated with higher delayed recall scores, and larger subiculum and CA4/dentate gyrus volumes were associated with fewer informant-reports of memory difficulties. There were no statistically significant associations between subfields and learning scores. Discussion Findings from the present study support the idea that difficulties with memory-dependent everyday tasks in older adults with MCI may signal a neurodegenerative process while increasing understanding of subfields correlates of these memory-specific functional difficulties. Continued investigations into identifying patterns of subfield atrophy in AD may aid early identification of those at higher risk of dementia conversion while advancing precision medicine. [ABSTRACT FROM AUTHOR]

Epileptic seizures result in pronounced over-expression of neuropeptide Y (NPY). In vivo and in vitro studies revealed that NPY exerts potent anticonvulsive actions through presynaptic Y2 receptors by suppressing glutamate release from principal neurons. We now investigated whether seizure-induced over-expression of NPY contributes to epileptic tolerance induced by preceding seizures. We used a previously established animal model based on selective inhibition of GABA release from parvalbumin (PV)-containing interneurons in the subiculum in mice. The animals present spontaneous recurrent seizures (SRS) and clusters of interictal spikes (IS). The frequency of SRS declined after five to six weeks, indicating development of seizure tolerance. In interneurons of the subiculum and sector CA1, SRS induced over-expression of NPY that persisted there for a prolonged time despite of a later decrease in SRS frequency. In contrast to NPY, somatostatin was not overexpressed in the respective axon terminals. Contrary to interneurons, NPY was only transiently expressed in mossy fibers. To demonstrate a protective function of endogenous, over-expressed NPY, we injected the selective NPY-Y2 receptor antagonist JNJ 5207787 simultaneously challenging the mice by a low dose of pentylenetetrazol (PTZ, 30 or 40 mg/kg, i.p.). In control mice, neither PTZ nor PTZ plus JNJ 5207787 induced convulsions. In mice with silenced GABA/PV neurons, PTZ alone only modestly enhanced EEG activity. When we injected JNJ 5207787 together with PTZ (either dose) the number of seizures, however, became significantly increased. In addition, in the epileptic mice CB1 receptor immunoreactivity was reduced in terminal areas of basket cells pointing to reduced presynaptic inhibition of GABA release from these neurons. Our experiments demonstrate that SRS result in overexpression of NPY in hippocampal interneurons. NPY overexpression persists for several weeks and may be related to later decreasing SRS frequency. Injection of the Y2 receptor antagonist JNJ 5207787 prevents this protective action of NPY only when release of the peptide is triggered by injection of PTZ and induces pronounced convulsions. Thus, over-expressed NPY released “on demand” by seizures may help terminating acute seizures and may prevent from recurrent epileptic activity.

The marmoset (a New World monkey) has recently received much attention as an experimental animal model; however, little is known about the connectivity of limbic regions, including cortical and hippocampal memory circuits, in the marmoset. Here, we investigated the neuronal connectivity of the marmoset, especially focusing on the connectivity between the hippocampal formation and the presubiculum, using retrograde and anterograde tracers (cholera toxin-B subunit and biotin dextran amine). We demonstrated the presence of a direct projection from the CA1 pyramidal cell layer to the deep layers of the presubiculum in the marmoset, which was previously identified in the rabbit brain, but not in the rat. We also found that the cells of origin of the subiculopresubicular projections were localized in the middle part along the superficial-to-deep axis of the pyramidal cell layer of the distal subiculum in the marmoset, which was similar to that in both rats and rabbits. Our results suggest that, compared to the rat and rabbit brains, connections between the hippocampal formation and presubiculum are highly organized and characteristic in the marmoset brain. [ABSTRACT FROM AUTHOR]

Preconditioning is a mechanism in which injuries induced by non‐lethal hypoxia or seizures trigger cellular resistance to subsequent events. Norwood et al., in a 2010 study, showed that an 8‐h‐long period of electrical stimulation of the perforant pathway in rats is required for the induction of hippocampal sclerosis. However, in order to avoid generalized seizures, status epilepticus (SE), and death, a state of resistance to seizures must be induced in the hippocampus by a preconditioning paradigm consisting of two daily 30‐min stimulation periods. Due to the importance of the subiculum in the hippocampal formation, this study aims to investigate differential gene expression patterns in the dorsal and ventral subiculum using RNA‐sequencing, after induction of a preconditioning protocol by electrical stimulation of the perforant pathway. The dorsal (dSub) and ventral (vSub) subiculum regions were collected by laser‐microdissection 24 h after preconditioning protocol induction in rats. RNA sequencing was performed in a Hiseq 4000 platform, reads were aligned using the STAR and DESEq2 statistics package was used to estimate gene expression. We identified 1176 differentially expressed genes comparing control to preconditioned subiculum regions, 204 genes were differentially expressed in dSub and 972 in vSub. The gene ontology enrichment analysis showed that the most significant common enrichment pathway considering up‐regulated genes in dSub and vSub was steroid metabolism. In contrast, the most significant enrichment pathway considering down‐regulated genes in vSub was axon guidance. Our results indicate that preconditioning induces changes in the expression of genes related to synaptic reorganization, increased cholesterol metabolism, and astrogliosis in both dSub and vSub. Both regions also presented a decrease in the expression of genes related to glutamatergic transmission and an increase in expression of genes related to complement system activation and GABAergic transmission. The down‐regulation of proapoptotic and axon guidance genes in the ventral subiculum suggests that preconditioning may induce a neuroprotective environment in this region. [ABSTRACT FROM AUTHOR]

Avoidance or anxiety-like behavior is accompanied by corresponding changes in hypothalamic-pituitary-adrenal (HPA) axis activation. The underlying neural circuitry for this coordinated behavioral and neuroendocrine control is not well established. Prior studies pointed to a neural projection from the ventral subiculum (vSub) to the bed nucleus of the stria terminalis (BNST) that can inhibit the HPA axis response to stress. Here, we used chemogenetics to investigate the role of vSub neurons and their projection to the anterior BNST (aBNST) in avoidance behavior and the accompanying corticosterone response in male and female mice. Surprisingly, we found that chemogenetic activation of ventral subiculum neurons increased the HPA axis response to an open field test in male and female mice, which was also seen with selective activation of vSub neurons projecting to the anterior BNST (vSub-aBNST neurons). On the other hand, VSub neuron and vSub-aBNST neuron activation had different effects on avoidance behavior, suggesting that the behavioral role of the VSub is variable and is dissociable from its neuroendocrine effects. In conclusion, our results reveal a surprising and novel role for the ventral subiculum in HPA axis activation via the anterior BNST. We also show that, like the ventral hippocampus, ventral subiculum neurons can increase or decrease avoidance behavior depending on their downstream projection. • Ventral subiculum neuron activity increases HPA axis reactivity to novelty stress via projections to the anterior BNST. • Ventral subiculum neurons can increase or decrease avoidance behavior depending on their downstream projection. • This is a novel effect of the ventral subiculum on HPA axis reactivity which is dissociable from its behavioral effects. • There are no sex differences in the role of the vSub in HPA axis activity and avoidance behavior. [ABSTRACT FROM AUTHOR]

In cities, the incidence of mental disorders is higher, while visits to nature have been reported to benefit mental health and brain function. However, there is a lack of knowledge about how exposure to natural and urban environments affects brain structure. To explore the causal relationship between exposure to these environments and the hippocampal formation, 60 participants were sent on a one hour walk in either a natural (forest) or an urban environment (busy street), and high-resolution hippocampal imaging was performed before and after the walks. We found that the participants who walked in the forest had an increase in subiculum volume, a hippocampal subfield involved in stress response inhibition, while no change was observed after the urban walk. However, this result did not withstand Bonferroni correction for multiple comparisons. Furthermore, the increase in subiculum volume after the forest walk was associated with a decrease in self-reported rumination. These results indicate that visits to nature can lead to observable alterations in brain structure, with potential benefits for mental health and implications for public health and urban planning policies. • Hippocampal subfield volume, the subiculum, increased after a one-hour walk in nature. • The subiculum volume did not change after the walk in the urban environment. • Subiculum volume change negatively linked to rumination change in the nature walk. [ABSTRACT FROM AUTHOR]

The mammillary bodies (MBOs), a group of hypothalamic nuclei, play a pivotal role in memory formation and spatial navigation. They receive extensive inputs from the hippocampus through the fornix, but the physiological significance of these connections remains poorly understood. Damage to the MBOs is associated with various forms of anterograde amnesia. However, information about the physiological characteristics of the MBO is limited, primarily due to the limited number of studies that have directly monitored MBO activity along with population patterns of its upstream partners. Employing large-scale silicon probe recording in mice, we characterize MBO activity and its interaction with the subiculum across various brain states. We find that MBO cells are highly diverse in their relationship to theta, ripple, and slow oscillations. Several of the physiological features are inherited by the topographically organized inputs to MBO cells. Our study provides insights into the functional organization of the MBOs. [Display omitted] • Mammillary body (MBO) cells show spatial gradients in coupling to hippocampal oscillations • Subicular inputs to the medial part of the MBO are denser and gradually weaken laterally • The location of MBO cells can be predicted based on coupling strength to hippocampal inputs • MBO cells poorly encode position but reliably encode the animal's running direction Employing large-scale recordings from the subiculum and mammillary bodies (MBOs), Nitzan and Buzsáki demonstrate that cells in the MBOs are differentially tuned to hippocampal oscillations such as theta waves and sharp-wave ripples. Using connectivity analysis, they show that those differences are due to a topographical organization of subicular inputs. [ABSTRACT FROM AUTHOR]

Subiculum is a pivotal output component of the hippocampal formation, a structure often overlooked in neuroscientific research. Here, this review aims to explore the role of the subiculum in various brain disorders, shedding light on its significance within the functional-neuroanatomical perspective on neurological diseases. The subiculum's involvement in multiple brain disorders was thoroughly examined. In Alzheimer's disease, subiculum alterations precede cognitive decline, while in epilepsy, the subiculum plays a critical role in seizure initiation. Stress involves the subiculum's impact on the hypothalamic-pituitary-adrenocortical axis. Moreover, the subiculum exhibits structural and functional changes in anxiety, schizophrenia, and Parkinson's disease, contributing to cognitive deficits. Bipolar disorder is linked to subiculum structural abnormalities, while autism spectrum disorder reveals an alteration of inward deformation in the subiculum. Lastly, frontotemporal dementia shows volumetric differences in the subiculum, emphasizing its contribution to the disorder's complexity. Taken together, this review consolidates existing knowledge on the subiculum's role in brain disorders, and may facilitate future research, diagnostic strategies, and therapeutic interventions for various neurological conditions. [Display omitted] • The role of the subiculum in various brain disorders was reviewed. • Subiculum exhibits structural and functional changes in brain disorders. • Neuronal circuits in subiculum mediate the memory and learning. • Progressive loss of subicular neurons was observed in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Brain imaging and genetics are fields acquiring data at increasing speed, but more information does not always result in a better understanding of the underlying biology. We developed the ProcessGeneLists (PGL) approach to use genetics and mRNA gene expression data to generate regions of interest for imaging studies. Methods: We applied PGL to past suicide attempt (ATT): We averaged the mRNA expression levels of genes (n = 130) possibly associated with ATT (p ≤ 10−3 in a published genome-wide association study, GWAS) in each brain region studied in the Human Allen Brain Atlas (6 ex-vivo brains, 158 to 946 regions/brain have mRNA expression data) and compared that to the averaged mRNA expression levels of all other genes in each region in each brain in the atlas. Results: PGL revealed 8 regions where "attempt-related genes" were differentially expressed (Wilcoxon test with Bonferroni correction 8.88−11 =

−6) and dorsolateral prefrontal cortex (dlPFC pFWE < 0.05) in ATT. We genotyped one single nucleotide polymorphism (SNP) in each of the five genes (within 130 from GWAS) with most important subicular expression. AKAP7 (A-Kinase Anchoring Protein 7, important in hippocampal memory processes) showed an interaction between genotype, ATT, and subiculum/dlPFC RSFC. Conclusion: PGL uncovered a brain function/genotype interaction in ATT by using published GWAS data to inform imaging studies. This could inform individualized therapies in the future. [ABSTRACT FROM AUTHOR]

Background: The hippocampus has for long been known for its ability to form new, declarative memory. However, emerging findings across conditions in the psychosis spectrum also implicate its role in emotional regulation. Systematic reviews have demonstrated consistent volume atrophic changes in the hippocampus. The aim of the systematic review and metanalysis which will follow from this protocol will be to investigate the volume-based neuroimaging findings across each of the subfields of the hippocampus in psychosis independent of diagnosis. Methods: Volume changes across subfields of the hippocampus in psychotic illnesses will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MRI neuroimaging studies of patients with a definitive diagnosis of psychosis (including brief pre-diagnostic states) will be included. Studies lacking adequate controls, illicit drug use, medical psychosis, history of other significant psychiatric comorbidities, or emphasis on age groups above 65 or below 16 will be excluded. Subfields investigated will include the CA1, CA2/3, CA4, subiculum, presubiculum, parasubiculum, dentate gyrus, stratum, molecular layer, granular cell layer, entorhinal cortex, and fimbria. Two people will independently screen abstracts from the output of the search to select suitable studies. This will be followed by the two reviewers performing a full-text review of the studies which were selected based on suitable abstracts. One reviewer will independently perform all the data extraction, and another reviewer will then systemically check all the extracted information using the original articles to ensure accuracy. Statistical analysis will be performed using the metafor and meta-packages in R Studio with the application of the random-effects model. Discussion: This study will provide insight into the volumetric changes in psychosis of the subfields of the hippocampus, independent of diagnosis. This may shed light on the intricate neural pathology which encompasses psychosis and will open avenues for further exploration of the structures identified as potential drivers of volume change. Systematic review registration: PROSPERO CRD42020199558 [ABSTRACT FROM AUTHOR]

Previous research on Physical Activity (PA) has been highly valuable in elucidating how PA affects the structure and function of the hippocampus in elderly populations that take part in structured interventions. However, how PA affects the hippocampus in younger populations that perform PA during daily-life activities remains poorly understood. In addition, this research has not examined the impact of PA on the internal structure of the hippocampus. Here, we performed a cross-sectional exploration of the way structural and functional aspects of the hippocampus are associated with habitual PA performed during work, leisure time, and sports in the daily lives of healthy young adults (n = 30; 14 female; mean age = 23.9 y.o.; SD = 7.8 y.o.). We assessed PA in these three different contexts through a validated questionnaire. The results show that PA performed during work time correlated with higher subicular volumes. In addition, we found that PA changed functional connectivity (FC) between a location in the middle/posterior hippocampus and regions of the default mode network, and between a location in the anterior hippocampus and regions of the somatomotor network. No statistical effects of PA performed during leisure time and sports were found. The results generalize the impact of PA on younger populations and show how PA performed in daily-life situations correlates with the precise internal structure and functional connectivity of the hippocampus. [ABSTRACT FROM AUTHOR]

Introduction: Hippocampal atrophy is an established Alzheimer's Disease (AD) biomarker. Volume loss in specific subregions as measurable with ultra-high field magnetic resonance imaging (MRI) may reflect earliest pathological alterations. Methods: Data from positron emission tomography (PET) for estimation of cortical amyloid β (Aβ) and high-resolution 7 Tesla T1 MRI for assessment of hippocampal subfield volumes were analyzed in 61 non-demented elderly individuals who were divided into risk-categories as defined by high levels of cortical Aβ and low performance in standardized episodic memory tasks. Results: High cortical Aβ and low episodic memory interactively predicted subicular volume [ F (3,57) = 5.90, p = 0.018]. The combination of high cortical Aβ and low episodic memory was associated with significantly lower subicular volumes, when compared to participants with high episodic memory (p = 0.004). Discussion: Our results suggest that low subicular volume is linked to established indicators of AD risk, such as increased cortical Aβ and low episodic memory. Our data support subicular volume as a marker of dementia-risk susceptibility in old-aged non-demented persons. [ABSTRACT FROM AUTHOR]

Simple Summary: Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most often refractory to medications. Electrical deep brain stimulation (DBS) has proved effective in controlling seizures in animal models and in drug-refractory MTLE patients. However, there is still no unifying framework for DBS parameters, which are obtained by trial-and-error and based on arbitrary, fixed stimulation frequencies rather than on physiologically relevant patterns. Interictal activity may present the key to devising personalized and physiologically relevant DBS strategies. Interictal activity occurs between seizures and is a hallmark of the hyperexcitability of the epileptic brain; depending on the underlying mechanisms and site of origin, it may promote seizures (pro-ictogenic) or dampen them (anti-ictogenic). In this work, we address the possibility of controlling seizure activity by means of electrical stimulation fashioned as a surrogate interictal pattern known to be anti-ictogenic. We show that this approach can effectively control seizure activity while delivering fewer electrical pulses than fixed-frequency stimulation. Thus, mimicking the temporal dynamics of an anti-ictogenic interictal pattern may represent a straightforward, personalized and more efficient DBS strategy to ameliorate drug-refractory epilepsy. Our work heralds a paradigm shift toward physiologically meaningful rather than arbitrary DBS parameters. Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most unresponsive to medications. Electrical deep brain stimulation (DBS) of the hippocampus has proved effective in controlling seizures in epileptic rodents and in drug-refractory MTLE patients. However, current DBS paradigms implement arbitrary fixed-frequency or patterned stimuli, disregarding the temporal profile of brain electrical activity. The latter, herein included hippocampal spontaneous firing, has been shown to follow lognormal temporal dynamics. Here, we present a novel paradigm to devise DBS protocols based on stimulation patterns fashioned as a surrogate brain signal. We focus on the interictal activity originating in the hippocampal subfield CA3, which has been shown to be anti-ictogenic. Using 4-aminopyridine-treated hippocampus-cortex slices coupled to microelectrode array, we pursue three specific aims: (1) address whether lognormal temporal dynamics can describe the CA3-driven interictal pattern, (2) explore the possibility of restoring the non-seizing state by mimicking the temporal dynamics of this anti-ictogenic pattern with electrical stimulation, and (3) compare the performance of the CA3-surrogate against periodic stimulation. We show that the CA3-driven interictal activity follows lognormal temporal dynamics. Further, electrical stimulation fashioned as a surrogate interictal pattern exhibits similar efficacy but uses less pulses than periodic stimulation. Our results support the possibility of mimicking the temporal dynamics of relevant brain signals as a straightforward DBS strategy to ameliorate drug-refractory epilepsy. Further, they herald a paradigm shift in neuromodulation, wherein a compromised brain signal can be recreated by the appropriate stimuli distribution to bypass trial-and-error studies and attain physiologically meaningful DBS operating modes. [ABSTRACT FROM AUTHOR]

Cross-sectional findings suggest that volumes of specific hippocampal subfields increase in middle childhood and early adolescence. In contrast, a small number of available longitudinal studies reported decreased volumes in most subfields over this age range. Further, it remains unknown whether structural changes in development are associated with corresponding gains in children’s memory. Here we report cross-sectional age differences in children’s hippocampal subfield volumes together with longitudinal developmental trajectories and their relationships with memory performance. In two waves, 109 participants aged 6–10 years (wave 1: MAge=7.25, wave 2: MAge=9.27) underwent high-resolution magnetic resonance imaging to assess hippocampal subfield volumes (imaging data available at both waves for 65 participants) and completed tasks assessing hippocampus dependent memory processes. We found that cross-sectional age-associations and longitudinal developmental trends in hippocampal subfield volumes were discrepant, both by subfields and in direction. Further, volumetric changes were largely unrelated to changes in memory, with the exception that increase in subiculum volume was associated with gains in spatial memory. Longitudinal and cross-sectional patterns of brain-cognition couplings were also discrepant. We discuss potential sources of these discrepancies. This study underscores that children’s structural brain development and its relationship to cognition cannot be inferred from cross-sectional age comparisons.

Previous research on Physical Activity (PA) has been highly valuable in elucidating how PA affects the structure and function of the hippocampus in elderly populations that take part in structured interventions. However, how PA affects the hippocampus in younger populations that perform PA during daily-life activities remains poorly understood. In addition, this research has not examined the impact of PA on the internal structure of the hippocampus. Here, we performed a cross-sectional exploration of the way structural and functional aspects of the hippocampus are associated with habitual PA performed during work, leisure time, and sports in the daily lives of healthy young adults (n = 30; 14 female; mean age = 23.9 y.o.; SD = 7.8 y.o.). We assessed PA in these three different contexts through a validated questionnaire. The results show that PA performed during work time correlated with higher subicular volumes. In addition, we found that PA changed functional connectivity (FC) between a location in the middle/posterior hippocampus and regions of the default mode network, and between a location in the anterior hippocampus and regions of the somatomotor network. No statistical effects of PA performed during leisure time and sports were found. The results generalize the impact of PA on younger populations and show how PA performed in daily-life situations correlates with the precise internal structure and functional connectivity of the hippocampus.

A comparative analysis of the targets for deep brain stimulation (DBS) to treat refractory temporal lobe epilepsy and the rationale for its use is presented, with an emphasis on the latency to obtain the significant antiepileptic effect and the long-term seizure control. The analysis includes consideration of surgical techniques currently used to optimize antiseizure effects and decrease surgical risks. Seizure control is similar for programed DBS and DBS responsive to abnormal cortical or subcortical electroencephalogram (EEG) activity. There is no difference in the long-term seizure control between programmed and responsive and intermittent or continuous DBS. However, intermittent programed DBS may have a significant antiseizure effect starting in the first month when applied to a non-sclerotic tissue such as the parahippocampal cortex. DBS induces no neuropsychological deterioration. [ABSTRACT FROM AUTHOR]