Hippocampal area CA2 activity supports social investigation following an acute social stress.

Neuronal activity in the hippocampus is critical for many types of memory acquisition and retrieval and influences an animal's response to stress. Moreover, the molecularly distinct principal neurons of hippocampal area CA2 are required for social recognition memory and aggression in mice. To interrogate the effects of stress on CA2-dependent behaviors, we chemogenetically manipulated neuronal activity in vivo during an acute, socially derived stressor and tested whether memory for the defeat was influenced.

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.

Preventative treatment for Alzheimer's Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear.

Prenatal exposure to the mineralocorticoid receptor antagonist spironolactone disrupts hippocampal area CA2 connectivity and alters behavior in mice.

In the brain, the hippocampus is enriched with mineralocorticoid receptors (MR; Nr3c2), a ligand-dependent transcription factor stimulated by the stress hormone corticosterone in rodents. Recently, we discovered that MR is required for the acquisition and maintenance of many features of mouse area CA2 neurons. Notably, we observed that immunofluorescence for the vesicular glutamate transporter 2 (vGluT2), likely representing afferents from the supramammillary nucleus (SuM), was disrupted in the embryonic, but not postnatal, MR knockout mouse CA2.

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.

Preventative treatment for Alzheimer's Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer's Disease remain unknown. In human patients with Alzheimer's Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer's Disease.

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice.

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout (, which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of knockout on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls.

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice.

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout ( -/-), which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of knockout ( -/-) on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls.

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.

Preventative treatment for Alzheimer's Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer's Disease remain unknown. In human patients with Alzheimer's Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer's Disease.

Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.

The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is an early site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC-NE loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown.

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.

Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-β (Aβ) and tau pathology are both abundant in the forebrain.

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease.

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms.

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice.

Exposure to unfamiliar odorants induces an array of repetitive defensive and non-defensive behaviors in rodents which likely reflect adaptive stress responses to the uncertain valence of novel stimuli. Mice genetically deficient for dopamine β-hydroxylase (Dbh-/-) lack the enzyme required to convert dopamine (DA) into norepinephrine (NE), resulting in globally undetectable NE and supranormal DA levels. Because catecholamines modulate novelty detection and reactivity, we investigated the effects of novel plant-derived odorants on repetitive behaviors in Dbh-/- mice and Dbh+/- littermate controls, which have catecholamine levels comparable to wild-type mice.

CRISPR-Cas9 editing of the arginine-vasopressin V1a receptor produces paradoxical changes in social behavior in Syrian hamsters.

Studies from a variety of species indicate that arginine–vasopressin (AVP) and its V1a receptor (Avpr1a) play a critical role in the regulation of a range of social behaviors by their actions in the social behavior neural network. To further investigate the role of AVPRs in social behavior, we performed CRISPR-Cas9–mediated editing at the Avpr1a gene via pronuclear microinjections in Syrian hamsters (Mesocricetus auratus), a species used extensively in behavioral neuroendocrinology because they produce a rich suite of social behaviors. Using this germ-line gene-editing approach, we generated a stable line of hamsters with a frame-shift mutation in the Avpr1a gene resulting in the null expression of functional Avpr1as.

Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer's Disease.

Background: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer's disease (AD) pathophysiology.

Objective: We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior.

Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives.

The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems.

Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome.

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null).

Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5.

Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus.

Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior.

Both the noradrenergic and galaninergic systems have been implicated in stress-related neuropsychiatric disorders, and these two neuromodulators are co-released from the stress-responsive locus coeruleus (LC); however, the individual contributions of LC-derived norepinephrine (NE) and galanin to behavioral stress responses are unclear. Here we aimed to disentangle the functional roles of co-released NE and galanin in stress-induced behavior. We used foot shock, optogenetics, and behavioral pharmacology in wild-type (WT) mice and mice lacking either NE (Dbh) or galanin (Gal) specifically in noradrenergic neurons to isolate the roles of these co-transmitters in regulating anxiety-like behavior in the elevated zero maze (EZM) either immediately or 24 h following stress.

Binding affinities of oxytocin, vasopressin and Manning compound at oxytocin and V1a receptors in male Syrian hamster brains.

Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, although their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioural and biomedical model for the study of OT and AVP and, more recently, hamsters have been used to investigate behavioural consequences of OT-mediated activation of V1aR. We aimed to determine the binding affinities of OT, AVP and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains.

Novel role for mineralocorticoid receptors in control of a neuronal phenotype.

Mineralocorticoid receptors (MRs) in the brain play a role in learning and memory, neuronal differentiation, and regulation of the stress response. Within the hippocampus, the highest expression of MRs is in area CA2. CA2 pyramidal neurons have a distinct molecular makeup resulting in a plasticity-resistant phenotype, distinguishing them from neurons in CA1 and CA3.

Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic δGABA receptors.

Rationale: Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABA receptors in the lateral septum have been shown to play a significant role in aggression in males.

Sex-dependent effects of social isolation on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5HT) 1a receptor binding and aggression.

It is widely held that social isolation produces higher rates of mortality and morbidity and has deleterious effects on an individual's sociality. Relatedly, it is widely observed that socially isolated adult rodents display significantly higher levels of aggression when placed in a social situation than do their conspecifics living in social groups. In the following study, we investigated the effects of social isolation on several neurochemical signals that play key roles in the regulation of social behavior in adults.

Modulation of CA2 neuronal activity increases behavioral responses to fear conditioning in female mice.

Activity of hippocampal pyramidal cells is critical for certain forms of learning and memory, and work from our lab and others has shown that CA2 neuronal activity is required for social cognition and behavior. Silencing of CA2 neurons in mice impairs social memory, and mice lacking Regulator of G-Protein Signaling 14 (RGS14), a protein that is highly enriched in CA2 neurons, learn faster than wild types in the Morris water maze spatial memory test. Although the enhanced spatial learning abilities of the RGS14 KO mice suggest a role for CA2 neurons in at least one hippocampus-dependent behavior, the role of CA2 neurons in fear conditioning, which requires activity of hippocampus, amygdala, and possibly prefrontal cortex is unknown.

Brain-derived neurotrophic factor signaling mitigates the impact of acute social stress.

Brain-derived neurotrophic factor (BDNF) is known to promote fear learning as well as avoidant behavioral responses to chronic social defeat stress, but, conversely, this peptide can also have antidepressant effects and can reduce depressant-like symptoms such as social avoidance. The purpose of this study was to use a variety of approaches to determine whether BDNF acting on tropomyosin receptor kinase B (TrkB) promotes or prevents avoidant phenotypes in hamsters and mice that have experienced acute social defeat stress. We utilized systemic and brain region-dependent manipulation of BDNF signaling before or immediately following social defeat stress in Syrian hamsters, TrkB knock-in mice, and C57Bl/6J mice and measured the subsequent behavioral response to a novel opponent.

Transcriptomic Analysis Reveals Sex-Dependent Expression Patterns in the Basolateral Amygdala of Dominant and Subordinate Animals After Acute Social Conflict.

The basolateral amygdala (BLA) is a critical nucleus mediating behavioral responses after exposure to acute social conflict. Male and female Syrian hamsters both readily establish a stable dominant-subordinate relationship among same-sex conspecifics, and the goal of the current study was to determine potential underlying genetic mechanisms in the BLA facilitating the establishment of social hierarchy. We sequenced the BLA transcriptomes of dominant, subordinate, and socially neutral males and females, and using de novo assembly techniques and gene network analyses, we compared these transcriptomes across social status within each sex.