Behavioral Phenotypes Research Articles

Salubrious effects of proanthocyanidins on behavioral phenotypes and DNA repair deficiency in the BTBR mouse model of autism

Autism is a neurodevelopmental disorder distinguished by impaired social interaction and repetitive behaviors. Global estimates indicate that autism affects approximately 1.6% of children, with the condition progressively becoming more prevalent over time. Despite noteworthy progress in autism research, the condition remains untreatable. This serves as a driving force for scientists to explore new approaches to disease management. Autism is linked to elevated levels of oxidative stress and disturbances in the DNA repair mechanism, which may potentially play a role in its comorbidities development. The current investigation aimed to evaluate the beneficial effect of the naturally occurring flavonoid proanthocyanidins on the behavioral characteristics and repair efficacy of autistic BTBR mice. Moreover, the mechanisms responsible for these effects were clarified. The present findings indicate that repeated administration of proanthocyanidins effectively reduces altered behavior in BTBR animals without altering motor function. Proanthocyanidins decreased oxidative DNA strand breaks and accelerated the rate of DNA repair in autistic animals, as evaluated by the modified comet test. In addition, proanthocyanidins reduced the elevated oxidative stress and recovered the disrupted DNA repair mechanism in the autistic animals by decreasing the expressions of Gadd45a and Parp1 levels and enhancing the expressions of Ogg1, P53, and Xrcc1 genes. This indicates that proanthocyanidins have significant potential as a new therapeutic strategy for alleviating autistic features.

GET73 modulates lipopolysaccharide- and ethanol-induced increase in cytokine/chemokine levels in primary cultures of microglia of rat cerebral cortex.

- Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia. - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8h, 37°C) or 75 mM ethanol (EtOH; 4 days, 37°C) alone or in the presence of GET73 (1-30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay). - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10-30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1-30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability. - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders.

Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses

Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we here investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subfield of the hippocampus.

The Role of Thioredoxin System in Shank3 Mouse Model of Autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, repetitive behaviors, and restricted interests. Unfortunately, the underlying molecular mechanism behind ASD remains unknown. It has been reported that oxidative and nitrosative stress are strongly linked to ASD. We have recently found that nitric oxide (NO•) and its products play an important role in this disorder. One of the key proteins associated with NO• is thioredoxin (Trx). We hypothesize that the Trx system is altered in the Shank3 KO mouse model of autism, which may lead to a decreased activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in oxidative stress, and thus, contributing to ASD-related phenotypes. To test this hypothesis, we conducted in vivo behavioral studies and used primary cortical neurons derived from the Shank3 KO mice and human SH-SY5Y cells with SHANK3 mutation. We showed significant changes in the levels and activity of Trx redox proteins in the Shank3 KO mice. A Trx1 inhibitor PX-12 decreased Trx1 and Nrf2 expression in wild-type mice, causing abnormal alterations in the levels of synaptic proteins and neurotransmission markers, and an elevation of nitrosative stress. Trx inhibition resulted in an ASD-like behavioral phenotype, similar to that of Shank3 KO mice. Taken together, our findings confirm the strong link between the Trx system and ASD pathology, including the increased oxidative/nitrosative stress, and synaptic and behavioral deficits. The results of this study may pave the way for identifying novel drug targets for ASD.

Integrin β1 in breast cancer: mechanisms of progression and therapy.

The therapy for breast cancer (BC), to date, still needs improvement. Apart from traditional therapy methods, biological therapy being explored opens up a novel avenue for BC patients. Integrin β1 (ITGβ1), one of the largest subgroups in integrin family, is a key player in cancer evolution and therapy. Recent researches progress in the relationship of ITGβ1 level and BC, finding that ITGβ1 expression evidently concerns BC progression. In this chapter, we outline diverse ITGβ1-based mechanisms regarding to the promoted effect of ITGβ1 on BC cell structure rearrangement and malignant phenotype behaviors, the unfavorable patient prognosis conferred by ITGβ1, BC therapy tolerance induced by ITGβ1, and lastly novel inhibitors targeting ITGβ1 for BC therapy.As an effective biomarker, ITGβ1 undoubtedly emerges one of targeted-therapy opportunities of BC patients in future. It is a necessity focusing on scientific and large-scale clinical trials on the validation of targeted-ITGβ1 drugs for BC patients.

Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer’s disease

BackgroundMicroglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer’s disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype.MethodsIn vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre−ERT2;Slc11a2flfl;APP/PS1+or – mice were generated and administered corn oil or tamoxifen to induce knockdown at 5–6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12–15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15–17 months) and bulk RNA-sequencing analysis was conducted.ResultsDMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KDAPP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KDAPP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α.ConclusionsThis work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KDAPP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.

Mapping the landscape of social behavior.

Social interaction is integral to animal behavior. However, we lack tools to describe it with quantitative rigor, limiting our understanding of its principles and neuropsychiatric disorders, like autism, that perturb it. Here, we present a technique for high-resolution 3D tracking of postural dynamics and social touch in freely interacting animals, solving the challenging subject occlusion and part assignment problems using 3D geometric reasoning, graph neural networks, and semi-supervised learning. We collected over 140 million 3D postures in interacting rodents, featuring new monogenic autism rat lines lacking reports of social behavioral phenotypes. Using a novel multi-scale embedding approach, we identified a rich landscape of stereotyped actions, interactions, synchrony, and body contact. This enhanced phenotyping revealed a spectrum of changes in autism models and in response to amphetamine that were inaccessible to conventional measurements. Our framework and large library of interactions will greatly facilitate studies of social behaviors and their neurobiological underpinnings.

A Selective Nuclear Factor-κB Inhibitor, JSH-23, Exhibits Antidepressant-like Effects and Reduces Brain Inflammation in Rats.

Accumulating evidence suggests that nuclear factor (NF)-κB is involved in the pathophysiology of mood disorders. We conducted two experimental protocols in rats to investigate the effects of a selective NF-κB inhibitor (JSH-23) on (i) lipopolysaccharide (LPS)-induced inflammation and (ii) on behavioral phenotypes in rat models of depression (sucrose consumption test and forced swim test) and mania (amphetamine-induced hyperactivity test). Additionally, we tested the effects of JSH-23 on levels of inflammatory components (interleukin-6, prostaglandin E2, nuclear phospho-p65, and tumor necrosis factor-α) in the brain. Acute treatment with JSH-23 (10 mg/kg, intraperitoneally [ip]) led to potent anti-inflammatory effects in LPS-treated rats, including a diminished hypothermic response to LPS and a reduction in pro-inflammatory mediators' levels in the brain. Chronic treatment with JSH-23 (3 mg/kg, ip, once daily, for 14 days) resulted in robust antidepressant-like effects (increased sucrose consumption and decreased immobility time). The antidepressant-like effects of JSH-23 were mostly accompanied by a reduction in levels of pro-inflammatory mediators in the brain. On the other hand, JSH-23 did not reduce amphetamine-induced hyperactivity. Altogether, these data suggest that NF-κB may be a potential therapeutic target for pharmacological interventions for depression.

Reduced multiscale complexity of daily behavioral dynamics in autism spectrum disorder.

Autism spectrum disorder (ASD) is difficult to diagnose objectively due to its heterogeneous and complex manifestations. This study aimed to objectively characterize the behavioral phenotypes of ASD children by exploring the multiscale behavioral dynamics. We applied behavioral organization (BO) and multiscale sample entropy (MSE) analyses to physical activity data collected from ASD and typically developing children, using wearable monitors in their daily life. We also examined their correlation with auditory startle response measures and clinical questionnaires, including the Social Responsiveness Scale (SRS) and the Strengths and Difficulties Questionnaire (SDQ). A significant decrease in MSE at timescales longer than 6 min was observed in ASD children, suggesting decreased irregularity or unpredictability, potentially linked to repetitive behaviors or stereotyped patterns commonly observed in ASD. Additionally, an increase in MSE positively correlated with prepulse inhibition levels, indicating its relationship with sensorimotor gating. Moreover, the observed significant negative correlation with the total difficulty score of SDQ substantiates MSE's potential as an objective metric for assessing general mental health problems associated with ASD. Multiscale analysis enhances the understanding of ASD's behavioral dynamics, providing valuable metrics for real-world assessments.

Human brain state dynamics are highly reproducible and associated with neural and behavioral features.

Neural activity and behavior vary within an individual (states) and between individuals (traits). However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatiotemporal features of co-activation patterns at the single-subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of occupying a particular co-activation pattern is reproducible and associated with neural and behavioral features. This combined analysis of state-trait variations holds promise for developing reproducible neuroimaging markers of individual life functional outcome.

Tau accumulation is cleared by the induced expression of VCP via autophagy.

Tauopathy, including frontotemporal lobar dementia and Alzheimer's disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAUP301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer's disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.

DCC in the cerebral cortex is required for cognitive functions in mouse.

Schizophrenia (SZ) is a highly heritable mental disorder, and genome-wide association studies have identified the association between deleted in colorectal cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p-AKT and p-GSK3α/β were decreased, which was responsible for impaired PPI in the DCC-deficient mice. Finally, the DCC-deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta-oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ-related risky gene and when defective, may promote SZ-like pathogenesis and behavioral phenotypes in mice.

Cognitive behavioral phenotyping of DSCAM heterozygosity as a model for autism spectrum disorder.

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM, as in the DSCAM2J+/-, that is, DSCAM heterozygous mice, displayed hyperactivity, increased anxiety-like behavior, and motor coordination deficits. Additionally, hippocampal-dependent learning and memory was affected, including impairments in working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM2J+/- as a suitable model for ASD research.

Cognitive effects of early life exposure to PCBs: Sex-specific behavioral, hormonal and neuromolecular mechanisms involving the brain dopamine system.

Endocrine-disrupting chemicals (EDCs) are environmental toxicants that disrupt hormonal and neurodevelopmental processes. Among these chemicals, polychlorinated biphenyls (PCBs) are particularly concerning due to their resistance to biodegradation and tendency to bioaccumulate. PCBs affect neurodevelopmental function and disrupt the brain's dopamine (DA) system, which is crucial for attentional, affective, and reward processing. These disruptions may contribute to the rising prevalence of DA-mediated neuropsychiatric disorders such as ADHD, depression, and substance use disorders. Notably, these behaviors are sexually dimorphic, in part due to differences in sex hormones and their receptors, which are targets of estrogenic PCBs. Therefore, this study determined effects of early life PCB exposure on behaviors and neurochemistry related to potential disruption of dopaminergic signaling. Male and female Sprague Dawley rats were exposed to PCBs or vehicle perinatally and then underwent a series of behavioral tests, including the sucrose preference test to measure affect, conditioned orienting to assess incentive-motivational phenotype, and attentional set-shifting to evaluate cognitive flexibility and response latency. Following these tests, rats were euthanized, and we measured serum estradiol (E2), midbrain DA cells, and gene expression in the midbrain. Female rats exposed perinatally to A1221 exhibited decreased sucrose preference, and both male and female A1221 rats had reduced response latency in the attentional set-shifting task compared to vehicle counterparts. Conditioned orienting, serum estradiol (E2), and midbrain DA cell numbers were not affected in either sex; however, A1221-exposed male rats displayed higher expression of estrogen receptor alpha ( Esr1 ) in the midbrain and non-significant effects on other DA-signaling genes. Additionally, E2 uniquely predicted behavioral outcomes and DAergic cell numbers in A1221-exposed female rats, whereas DA signaling genes were predictive of behavioral outcomes in males. These data highlight sex-specific effects of A1221 on neuromolecular and behavioral phenotypes.

Alterations in cortical and subcortical neuroanatomy and associations with behavior in females with fragile X syndrome.

To address substantial gaps in the literature on neuroanatomical variations in females with fragile X syndrome (FXS). Surface-based modeling techniques were applied to the magnetic resonance imaging of 45 females with FXS (mean age = 10 years 9 months, range 6 years-16 years 4 months, SD = 2 years 9 months) and 33 age-matched and developmentally matched females without FXS to elucidate differences in cortical gray matter volume, surface area, and thickness. Gray matter volumes in subcortical regions were examined to ascertain differences in subcortical volume. In females with FXS, cortical volume was greater bilaterally in the occipital pole and smaller in the right postcentral gyrus. Seven regions demonstrated lower surface area in participants with FXS, while cortical thickness was significantly greater over the posterior and medial surfaces in the group with FXS. Subcortical region of interest analyses demonstrated greater volume in the caudate nucleus, globus pallidus, and nucleus accumbens in the group with FXS. Global gray matter volume, pial thickness, and surface area were associated with behavioral outcomes in the group with FXS but not in the comparison group. Females with FXS demonstrated unique cortical and subcortical gray matter anatomy relative to a matched comparison group. These findings may be relevant to the pathogenesis of the FXS behavioral phenotype and provide insights into behavioral interventions targeted to this population.

Contrasting Effects of Oxytocin on MK801-Induced Social and Non-Social Behavior Impairment and Hyperactivity in a Genetic Rat Model of Schizophrenia-Linked Features.

Social withdrawal in rodents is a measure of asociality, an important negative symptom of schizophrenia. The Roman high- (RHA) and low-avoidance (RLA) rat strains have been reported to exhibit differential profiles in schizophrenia-relevant behavioral phenotypes. This investigation was focused on the study of social and non-social behavior of these two rat strains following acute administration of dizocilpine (MK801, an NMDA receptor antagonist), a pharmacological model of schizophrenia-like features used to produce asociality and hyperactivity. Also, since oxytocin (OXT) has been proposed as a natural antipsychotic and a potential adjunctive therapy for social deficits in schizophrenia, we have evaluated the effects of OXT administration and its ability to reverse the MK801-impairing effects on social and non-social behavior and MK801-induced hyperactivity. MK801 administration produced hyperlocomotion and a decrease in social and non-social behavior in both rat strains, but these drug effects were clearly more marked in RHA rats. OXT (0.04 mg/kg and 0.2 mg/kg) attenuated MK801-induced hyperlocomotion in both rat strains, although this effect was more marked in RHA rats. The MK801-decreasing effect on exploration of the "social hole" was moderately but significantly attenuated only in RLA rats. This study is the first to demonstrate the differential effects of OXT on MK801-induced impairments in the two Roman rat strains, providing some support for the potential therapeutic effects of OXT against schizophrenia-like symptoms, including both a positive-like symptom (i.e., MK801-induced hyperlocomotion) and a negative-like symptom (i.e., MK801 decrease in social behavior), while highlighting the importance of the genetic background (i.e., the rat strain) in influencing the effects of both MK801 and oxytocin.

Low Sun Exposure Is Associated with Both Progressive-Onset and Relapse-Onset Multiple Sclerosis Risk: A Case-Control Study

Background: Sun exposure has consistently been associated with multiple sclerosis (MS) onset, but case samples are predominantly relapse-onset MS (ROMS), and risk estimates have rarely been reported separately for ROMS and progressive-onset MS (POMS). We aimed to determine whether sun exposure prior to disease onset was associated with POMS and whether the effect differed between POMS and ROMS. Methods: This nationwide case-control study included 153 POMS cases, 204 incident ROMS cases, and 558 community controls with data from two separate datasets: the PPMS Study (2015–2021) and the Ausimmune Study (2003–2006). Information on time spent in the sun before the first MS symptom, skin phenotype, and sun protection behavior was collected. Satellite data on ambient ultraviolet radiation (UVR) were used to calculate cumulative UVR dose. Unconditional logistic regression was used with adjustment for covariates. Results: There were consistent dose-response associations, with higher levels of UVR exposure associated with a reduced risk of POMS, both for leisure-time and occupational UVR from age 6 to symptom onset. Associations were overall stronger for POMS than ROMS. For example, cumulative leisure-time UVR dose (per 100 kJ/m2 increment) was associated with POMS (aOR 0.93, 95% CI: 0.91–0.95) and the association was slightly weaker for ROMS (aOR 0.96, 95% CI: 0.94–0.99) for age 6 to symptom onset (test for interaction p < 0.001). Conclusions: Low levels of sun exposure, throughout the whole lifespan, are associated with an increased risk of POMS and ROMS onset. The sun effects are usually stronger for POMS than ROMS.

The functional role of locus coeruleus microglia in the female stress response.

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress, and ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

Drift in Individual Behavioral Phenotype as a Strategy for Unpredictable Worlds.

Why do individuals animals spontaneously change their preferences over time? While stable idiosyncratic behavioral preferences have been proposed to help species survive unpredictable environments as part of a bet-hedging strategy, the role of intraindividual shifts in preferences is unclear. Using Drosophila melanogaster , we show the stability of individual preferences is influenced by genetic background and neuromodulation, and is therefore a regulated phenomenon. We use theoretical modeling to show that shifts in preferences may be adaptive to environments that change within an individual's lifespan, including many real world patterns of environmental fluctuations. Together, this work suggests that the stability of individual preferences may affect the survival of species in unpredictable worlds - understanding that may be increasingly important in the face of anthropogenic change.

Bipolar Disorder in a female with CDKL5 Deficiency Disorder: A Case Report.

CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation. We aimed to identify the clinical characteristics of an individual with CDD who presented with a mood disorder falling outside this expected behavioral phenotype. We identified one 22-year-old female with CDD diagnosed with unspecified bipolar disorder at 18 years of age. Family history was noncontributory. At diagnosis, she had fluctuations in mood, characterized by periods of elated affect, increased energy and vocalizations, hypertonia, and insomnia lasting 3-4 days alternating with periods of depressed affect, irritability, hypotonia, and excessive sleep lasting for up to one month. She had experienced frequent mood swings and sleep dysregulation from early childhood, and by early adulthood the duration of "up" and "down" periods fell in the range specified in the DSM-5 bipolar disorder criteria. Trazodone and suvorexant did not alleviate sleep related symptoms. Her epilepsy was well controlled on lamotrigine monotherapy since early childhood. Though lamotrigine treatment has had no psychiatric benefit despite its known mood stabilizing properties, aripiprazole has been effective in reducing severity and frequency of fluctuations between hypomania and depression. While sleep and behavioral disorders fall within the expected phenotype for CDD, this is the first report of bipolar disorder. Careful attention to patterns of sleep and behavior that may indicate mood cycling in this population is required, particularly in the setting of limited communication and functional abilities.