Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor FosB/ΔFosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of FosB/ΔFosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ΔFosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification to assess cocaine-induced, FosB/ΔFosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a FosB/ΔFosB-dependent increase in the expression of calreticulin, an endoplasmic reticulum-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a noncanonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

Oxytocin is a neuropeptide that can promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neurons. An outstanding question is whether these behavioral effects are also driven by distinct or overlapping populations of oxytocin-producing neurons. The paraventricular nucleus (PVN) of the hypothalamus is a major source of oxytocin and sends projections to the mesolimbic dopamine system and extended amygdala. Previous work found that social defeat stress increased oxytocin neuron activity in the anterior PVN (aPVN) but not posterior PVN (pPVN). We reduced oxytocin synthesis with antisense morpholino oligonucleotides in either anterior or posterior PVN in California mice (Peromyscus californicus), a strong model system for studying effects of social stress on brain function and behavior. Antisense morpholinos in aPVN had no effect on behavior in unstressed females but increased social approach and reduced social vigilance in females exposed to social defeat stress. In pPVN, antisense morpholinos reduced social approach in unstressed male and female California mice. We then used OxtCre mice to compare electrophysiological profiles of oxytocin in aPVN and pPVN with a population of oxytocin neurons in the bed nucleus of the stria terminalis (BNST). Oxytocin neurons in aPVN and BNST had higher post-synaptic events and responded more strongly to current injections than oxytocin neurons in pPVN, though they had similar excitatory and inhibitory input balance at the observed resting membrane potential. These findings shed light on to functional and physiological heterogeneity of PVN oxytocin neurons. Our results suggest that context-dependent behavioral effects of oxytocin are mediated by different populations of oxytocin neurons.

BACKGROUND:Astrocytes in the nucleus accumbens (NAc) play a dynamic role in regulating synaptic plasticity induced by drugs of abuse through modulation of glutamatergic neurotransmission. Astrocyte-secreted factors may also contribute to the reprogramming of brain circuitry that leads to drug-seeking behavior. Here, we investigated the role of astrocyte Ca2+ signals in vivo and of the astrocyte-secreted protein hevin in the rewarding properties of cocaine. METHODS:Ca2+ signals in NAc astrocytes were measured by in vivo fiber photometry during conditioned place preference (CPP) to cocaine. Depletion of Ca2+ and chemogenetic activation were used to evaluate the contribution of astrocyte Ca2+ signals to cocaine CPP. The effects of cocaine in hevin-null mice and after hevin knockdown in NAc astrocytes were evaluated by imaging of medium spiny neuron spines, electrophysiology, and CPP. Hevin secretion was monitored by light-sheet imaging in brain slices. RESULTS:Cocaine increased the amplitude of Ca2+ signals in astrocytes during conditioning. Attenuating Ca2+ signals in astrocytes prevented cocaine CPP, whereas augmenting these signals potentiated this conditioning. Astrocyte activation induced a surge in hevin secretion ex vivo. Hevin knockdown in NAc astrocytes led to a decrease in CPP and in structural and synaptic plasticity induced by cocaine in medium spiny neurons. CONCLUSIONS:These findings reveal a fine-tuning by cocaine of in vivo Ca2+ signals in NAc astrocytes. Astrocyte Ca2+ signals are sufficient and necessary for the acquisition of cocaine-seeking behavior. Hevin can be released upon astrocyte activation and is a major effector of the action of cocaine and Ca2+ signals on reward and neuronal plasticity.

The lateral entorhinal cortex (LEC) contains glutamatergic projections that innervate the nucleus accumbens (NAc) and may be involved in the encoding of contextual associations with both positive and negative valences, such as those encountered in drug cues or fear conditioning. To determine whether LEC-NAc neurons are activated by the encoding and recall of contexts associated with cocaine or footshock, we measured c-fos expression in these neurons and found that LEC-NAc neurons are activated in both contexts. Specifically, activation patterns of the LEC-NAc were observed in a novel context and reexposure to the same context, highlighting the specific role for LEC-NAc neurons in encoding rather than the valence of a specific event-related memory. Using a combination of circuit-specific chemogenetic tools and behavioral assays, we selectively inactivated LEC-NAc neurons in mice during the encoding and retrieval of memories of contexts associated with cocaine or footshock. Chemogenetic inactivation of LEC-NAc neurons impaired the formation of both positive and negative context-associated memories without affecting the retrieval of an established memory. This finding suggests a critical role for this circuit in the initial encoding of contextual associations. In summary, LEC-NAc neurons facilitate the encoding of contextual information, guiding motivational behaviors without directly mediating the hedonic or aversive properties of these associations.

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer’s disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor ΔFosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but it's function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of ΔFosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ΔFosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosomal affinity purification (TRAP) to assess cocaine-induced, ΔFosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a ΔFosB-dependent increase in the expression of calreticulin, an ER-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a novel, non-canonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward. ### Competing Interest Statement The authors have declared no competing interest.

The lateral hypothalamic area (LHA) is essential for ingestive behavior but has primarily been studied in modulating feeding, with comparatively scant attention on drinking. This is partly because most LHA neurons simultaneously promote feeding and drinking, suggesting that ingestive behaviors track together. A notable exception are LHA neurons expressing neurotensin (LHA(Nts) neurons): activating these neurons promotes water intake but modestly restrains feeding. Here we investigated the connectivity of LHA(Nts) neurons, their necessity and sufficiency for drinking and feeding, and how timing and resource availability influence their modulation of these behaviors. LHA(Nts) neurons project broadly throughout the brain, including to the lateral preoptic area (LPO), a brain region implicated in modulating drinking behavior. LHA(Nts) neurons also receive inputs from brain regions implicated in sensing hydration and energy status. While activation of LHA(Nts) neurons is not required to maintain homeostatic water or food intake, it selectively promotes drinking during the light cycle, when ingestive drive is low. Activating LHA(Nts) neurons during this period also increases willingness to work for water or palatable fluids, regardless of their caloric content. By contrast, LHA(Nts) neuronal activation during the dark cycle does not promote drinking, but suppresses feeding during this time. Finally, we demonstrate that the activation of the LHA(Nts) -> LPO projection is sufficient to mediate drinking behavior, but does not suppress feeding as observed after generally activating all LHA(Nts) neurons. Overall, our work suggests how and when LHA(Nts) neurons oppositely modulate ingestive behaviors

With an incidence of -1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Perinatal mental health difficulties affect approximately 20% of women and the impact on women and children costs the UK £8.1 billion per annual cohort of births (Bauer et al., 2014). For some women these difficulties occur for the first time in the perinatal period, while others have pre-existing mental health conditions. Conditions range from mild to moderate depression or anxiety to more severe conditions, such as post-traumatic stress disorder, psychosis and bipolar disorder. The question posed is how best to support women with newly emergent psychological difficulties as well as prevent the reemergence of symptoms in those with a history of mental health difficulties. Most evidence on interventions for perinatal mental health difficulties is based on studies examining the efficacy of a single intervention such as exercise, meditation or psychotherapy. However, it is unlikely that any single intervention will be appropriate for all women given the diversity in symptoms and severity, as well as women’s individual and social circumstances. This may explain why some studies suggest an intervention that is not universally effective may be effective for some women, e.g. the HABiT study of expressive writing (Ayers et al., 2018). It is therefore important to move away from a ‘one-size fits all’ approach to a personalised approach, which means offering a range of different interventions. Personalised medicine ‘uses new approaches to better manage patients’ health and target therapies to achieve the best outcomes in the management of a patient’s disease or predisposition to disease’ (NHS England, 2016). Personalised and person-centred approaches have been used throughout medicine, but advances in genomics and informatics mean the field is advancing rapidly. This is especially the case in relation to physical illnesses, such as cancer (Gambardella et al., 2020). Personalised approaches might deliver better health outcomes and provide a way to address equality of access for different sociodemographic groups and offer treatments suitable for the needs of local populations. The UK Long Term Plan (LTP) committed to delivering personalised care by 2024 (NHS, 2019). The six principles of personalised care are: (1) patient choice; (2) shared decision making; (3) patient activation and supported selfmanagement; (4) social prescribing and community based support; (5) personalised care and support planning; and (6) personal health budgets. If women are currently well, the LTP recommends using patient choice, shared decision making, social prescribing and community support to increase well-being and prevent ill-health. If women have complications or longterm conditions, the LTP recommends also using patient activation and self-management, personalised care and support planning to increase the likelihood of good outcomes. So what might personalised care for perinatal mental health look like? First, it would involve offering a range of interventions, in a range of settings. Improving Access to Psychological Therapies services, which provide targeted cognitive behaviour therapy JOURNAL OF REPRODUCTIVE AND INFANT PSYCHOLOGY 2021, VOL. 39, NO. 4, 339–341 https://doi.org/10.1080/02646838.2021.1962614

The Akt family of kinases exerts many of its cellular effects via the activation of the mammalian target of rapamycin (mTOR) kinase through a series of intermediary proteins. Multiple lines of evidence have identified Akt-family kinases as candidate schizophrenia and bipolar disorder genes. Although dysfunction of the prefrontal cortex (PFC) is a key feature of both schizophrenia and bipolar disorder, no studies have comprehensively assessed potential alterations in Akt-mTOR pathway activity in the PFC of either disorder. Here, we examined the activity and expression profile of key proteins in the Akt-mTOR pathway in bipolar disorder and schizophrenia homogenates from two different PFC subregions. Our findings identify reduced Akt-mTOR PFC signaling in a subset of bipolar disorder subjects. Using a reverse-translational approach, we demonstrated that Akt hypofunction in the PFC is sufficient to give rise to key cognitive phenotypes that are paralleled by alterations in synaptic connectivity and function.

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.

Regardless of personal risk, engaging with shocking and threatening stimuli is the job of law enforcement officers, thereby exposing officers to risk for stress-related health conditions. Stress vulnerability is a result of pathophysiological changes in the body's stress systems which can lead to stress sensitization and impairments in evaluating environmental stressors. Through such mechanisms, chronic stress can have deleterious health consequences; however, a portion of individuals exposed to stress and/or trauma successfully adapt and demonstrate resilience, and this resilience is an active physiological process mediated in part by the reward circuitry of the brain. In the chapter that follows, both systemic and brain-specific stress physiology will be reviewed as it relates to law enforcement work-related exposures and stress-related health conditions. Mechanisms of stress resilience and how to leverage physiological data to optimize police training will also be reviewed.

Neural proliferation in the dentate gyrus (DG) is closely linked with learning and memory, but the transcriptional programming that drives adult proliferation remains incompletely understood. Our lab previously elucidated the critical role of the transcription factor ΔFosB in the dorsal hippocampus (dHPC) in learning and memory, and the FosB gene has been suggested to play a role in neuronal proliferation. However, the subregion-specific and potentially cell-autonomous role of dHPC ΔFosB in neurogenesis-dependent learning has not been studied. Here, we crossed neurotensin receptor-2 (NtsR2) Cre mice, which express Cre within the subgranular zone (SGZ) of dHPC DG, with floxed FosB mice to show that knockout of ΔFosB in hippocampal SGZ neurons reduces antidepressant-induced neurogenesis and impedes hippocampus-dependent learning in the novel object recognition task. Taken together, these data indicate that FosB gene expression in SGZ is necessary for both hippocampal neurogenesis and memory formation.

Drug addiction is characterized by compulsive drug seeking and drug intake despite adverse consequences. Although abuse of both licit and illicit substances is estimated to cost over $700 billion annually in health care, crime, and lost productivity in the United States alone, there are currently few pharmacological treatments for drug addiction, and those that do exist have low efficacy in many individuals. This paucity of effective treatment options may be due to inextirpable drug-induced changes in brain function that drive some or all of the addiction phenotype. Chronic drug exposure associated with addiction induces persistent changes in the structure and function of brain cells and circuits that underlie addictive behavior, for example, drug seeking and relapse. Therefore, identifying target mechanisms that drive long-term functional changes in the brain is a critical step in illuminating disease etiology and developing new treatments. This will require a comprehensive understanding of the neurobiology of addiction, including the role of gene expression, and its regulation, in drug-induced changes in neuronal structure and function. We will summarize in the subsequent chapter the transcriptional and epigenetic mechanisms of addiction and, furthermore, we will discuss the current implications of these findings in terms of prevention of drug addiction and drug discovery for the treatment of addiction.

Drug addiction results in part from maladaptive learning, including the formation of strong associations between the drug and the circumstances of consumption. However, drug-induced changes in gene expression underlying the saliency of these associations remain understudied. Consolidation of explicit memories occurs within the hippocampus, and we have shown that spatial learning induces expression of the transcription factor ΔFosB in hippocampus and that this induction is critical for learning. Drugs of abuse also upregulate ΔFosB in hippocampus, but the mechanism of its induction by cocaine and its role in hippocampus-dependent cocaine responses is unknown. We investigated differences in mouse dorsal and ventral hippocampal ΔFosB expression in response to chronic cocaine, because these regions appear to regulate distinct cocaine-related behaviors. We found that cocaine-mediated induction of ΔFosB was subregion-specific, and that ΔFosB transcriptional activity in both the dorsal and ventral hippocampus is necessary for cocaine conditioned place preference. Further, we characterize changes in histone modifications at the FosB promoter in hippocampus in response to chronic cocaine and found that locus-specific epigenetic modification is essential for FosB induction and multiple hippocampus-dependent behaviors, including cocaine place preference. Collectively, these findings suggest that exposure to cocaine induces histone modification at the hippocampal FosB gene promoter to cause ΔFosB induction critical for cocaine-related learning.SIGNIFICANCE STATEMENT Although cocaine addiction is driven in part by the formation of indelible associations between the drug and the environment, paraphernalia, and circumstances of use, and although this type of associative learning is dependent upon changes in gene expression in a brain region called the hippocampus, the mechanisms by which cocaine alters hippocampal gene expression to drive formation of these associations is poorly understood. Here, we demonstrate that chronic cocaine engages locus-specific changes in the epigenetic profile of the FosB gene in the hippocampus, and that these alterations are required for cocaine-dependent gene expression and cocaine-environment associations. This work provides novel insight into addiction etiology and potential inroads for therapeutic intervention in cocaine addiction.

BACKGROUND: Depression affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Preclinical studies in male mice suggest that activity of ventral hippocampus (vHPC) neurons projecting to the nucleus accumbens (NAc) regulates mood-related behavioral responses to stress. We sought to characterize this circuit in both sexes and to investigate its role in potential sex differences in models of depression. METHODS: We used male and female adult C57BL/6J mice in the subchronic variable stress model to precipitate female-specific reduction in sucrose preference and performed gonadectomies to test the contributions of gonadal hormones to this stress response. In addition, ex vivo slice electrophysiology of transgenic Cre-inducible Rosa-eGFP-L10a mice in combination with retrograde viral tracing to identify circuits was used to test contributions of gonadal hormones to sex differences in vHPC afferents. Finally, we used an intersecting viral DREADD (designer receptor exclusively activated by designer drugs) strategy to manipulate vHPC-NAc excitability directly in awake behaving mice. RESULTS: We show a testosterone-dependent lower excitability in male versus female vHPC-NAc neurons and corresponding testosterone-dependent male resilience to reduced sucrose preference after subchronic variable stress. Importantly, we show that long-term DREADD stimulation of vHPC-NAc neurons causes decreased sucrose preference in male mice after subchronic variable stress, whereas DREADD inhibition of this circuit prevents this effect in female mice. CONCLUSIONS: We demonstrate a circuit-specific sex difference in vHPC-NAc neurons that is dependent on testosterone and causes susceptibility to stress in female mice. These data provide a substantive mechanism linking gonadal hormones to cellular excitability and anhedonia-a key feature in depressive stress.