Reduction in vasopressin cells in the suprachiasmatic nucleus in mice increases anxiety and alters fluid intake.

Central vasopressin (AVP) has been implicated in the control of multiple behaviors, including social behavior, anxiety-like behavior, and sickness behavior. The extent to which the different AVP-producing cell groups contribute to regulating these behaviors has not been extensively investigated. Here we test the role of AVP cells in the suprachiasmatic nucleus (SCN) in these behaviors by ablating these cells using viral-mediated, Cre-dependent caspase in male and female AVP-Cre + mice and Cre-controls. We compared anxiety and social behaviors, as well as sickness behaviors (lethargy, anhedonia (indexed by sucrose consumption), and changes in anxiety-like- and social behavior) induced via injection of bacterial lipopolysaccharide (LPS). We found that SCN AVP cell ablation increased anxiety-like behavior and sucrose consumption in both sexes, as well as increased urine marking by males in a non-social context, but did not alter behavioral responses to sickness. Our data suggest that SCN AVP does not strongly affect LPS-induced behavioral changes, but may contribute to anxiety-like behavior, and may play a role in ingestive reward/motivation and fluid intake.

Sex Differences in the Control of Social Investigation and Anxiety by Vasopressin Cells of the Paraventricular Nucleus of the Hypothalamus.

The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, but the source of AVP release relevant for behavior has not been precisely determined. Potential sources include hypothalamic cell populations such as the paraventricular (PVN), supraoptic, and suprachiasmatic nuclei, as well as extrahypothalamic cell groups in the extended amygdala. To address if AVP-expressing cells in the PVN are important for mouse social communication, we deleted PVN AVP-expressing cells using viral-mediated delivery of Cre-dependent caspase-9 cell death construct into the PVN of AVP-Cre-positive mice (expressing Cre-recombinase under the control of the AVP promoter) or AVP-Cre-negative littermate controls, and assessed their levels of social investigation, social communication, anxiety, sex behavior, and aggressive behavior. We found that these lesions increased social investigation in females, but not in males. However, in males but not in females, these lesions increased non-social anxiety-related behaviors in the elevated-plus maze. These results therefore point at differential involvement of PVN AVP-expressing cells in the context of social and emotional behavior in the two sexes, which may contribute to sex differences in social communication and anxiety disorders.

Sexually dimorphic role of BNST vasopressin cells in sickness and social behavior in male and female mice.

Circumstantial evidence supports the hypothesis that the sexually dimorphic vasopressin (AVP) innervation of the brain tempers sickness behavior in males. Here we test this hypothesis directly, by comparing sickness behavior in animals with or without ablations of BNST AVP cells, a major source of sexually dimorphic AVP in the brain. We treated male and female AVP-iCre+ and AVP-iCre- mice that had been injected with viral Cre-dependent caspase-3 executioner construct into the BNST with lipopolysaccharide (LPS) or sterile saline, followed by behavioral analysis. In all groups, LPS treatment reliably reduced motor behavior, increased anxiety-related behavior, and reduced sucrose preference and consumption. Male mice, whose BNST AVP cells had been ablated (AVP-iCre+), displayed only minor reductions in LPS-induced sickness behavior, whereas their female counterparts displayed, if anything, an increase in sickness behaviors. All saline-treated mice with BNST AVP cell ablations consumed more sucrose than did control mice, and males, but not females, with BNST AVP cell ablations showed reduced preference for novel conspecifics compared to control mice. These data confirm that BNST AVP cells control social behavior in a sexually dimorphic way, but do not play a critical role in altering sickness behavior.

Exposure to female pheromones stimulates a specific type of neuronal population in the male but not female magnocellular division of the medial preoptic nucleus (MPN mag) of the Syrian hamster.

The magnocellular division of the medial preoptic area (MPN mag) integrates pheromonal and hormonal signals to play a critical role in the expression of male typical sex behavior. The MPN mag contains two morphologically distinct neuronal populations; the percentage of each type within the nucleus is sex specific. Males have more neurons with a single nucleolus whereas females have more with multiple nucleoli. To determine which neuronal subtype mediates pheromonal induction of copulation, tissue from male and female hamsters exposed to female pheromones was immunolabeled for the immediate early protein (EGR-1). Subsequently the tissue was counterstained and the number of ERG-1 neurons with one or two nuclei was determined. The results indicate that pheromones stimulate neurons with single nucleoli in males but fail to stimulate either neuronal subtype in females suggesting that synaptic input to the MPN mag is sexually differentiated.

Removal of vasopressin cells from the paraventricular nucleus of the hypothalamus enhances lipopolysaccharide-induced sickness behaviour in mice.

Vasopressin (AVP) cells in the paraventricular nucleus of the hypothalamus (PVN) are activated during sickness and project to multiple nuclei responsible for the anxiety, social and motivated behaviours affected during sickness, suggesting that these cells may play a role in sickness behaviours, typically expressed as reduced mobility, increased anxiety, anhedonia and social withdrawal. In the present study, we selectively ablated AVP neurones in the PVN of male and female mice (Mus musculus) and induced sickness behaviour via injection of bacterial lipopolysaccharide (LPS). We found that PVN AVP ablation increased the effects of LPS, specifically by further decreasing sucrose preference in males and females and decreasing the social preference of males, monitored within 24 hours of LPS injection. These results suggest that PVN AVP contributes to the change in motivated behaviours during sickness and may help promote recovery from infection..

Sexually Dimorphic Vasopressin Cells Modulate Social Investigation and Communication in Sex-Specific Ways.

The neuropeptide arginine vasopressin (AVP) has long been implicated in the regulation of social behavior and communication, but precisely which AVP cell groups are involved is largely unknown. To address whether the sexually dimorphic AVP cell group in the bed nucleus of the stria terminalis (BNST) is important for social communication, we deleted BNST AVP cells by viral delivery of a Cre-dependent caspase-3 cell-death construct in AVP-iCre-positive mice using AVP-iCre negative littermate as controls, and assessed social, sexual, aggressive and anxiety-related behaviors. In males, lesioning BNST AVP cells reduced social investigation of other males and increased urine marking (UM) in the presence of a live female, without altering ultrasonic vocalizations (USVs), resident-intruder aggression, copulatory behavior, anxiety, or investigation of females or their odor cues. In females, which have significantly fewer AVP cells in the BNST, these injections influenced copulatory behavior but otherwise had minimal effects on social behavior and communication, indicating that these cells contribute to sex differences in social behavioral function.

Dietary emulsifiers consumption alters anxiety-like and social-related behaviors in mice in a sex-dependent manner.

Dietary emulsifiers carboxylmethylcellulose (CMC) and polysorbate 80 (P80) alter the composition of the intestinal microbiota and induce chronic low-grade inflammation, ultimately leading to metabolic dysregulations in mice. As both gut microbiota and intestinal health can influence social and anxiety-like behaviors, we investigated whether emulsifier consumption would detrimentally influence behavior. We confirmed that emulsifier exposure induced chronic intestinal inflammation, increased adiposity, and altered gut microbiota composition in both male and female mice, although the specific microboal taxa altered following emulsifier consumption occurred in a sex-dependent manner. Importantly, emulsifier treatment altered anxiety-like behaviors in males and reduced social behavior in females. It also changed expression of neuropeptides implicated in the modulation of feeding as well as social and anxiety-related behaviors. Multivariate analyses revealed that CMC and P80 produced distinct clustering of physiological, neural, and behavioral effects in male and female mice, suggesting that emulsifier treatment leads to a syndrome of sex-dependent changes in microbiota, physiology, and behavior. This study reveals that these commonly used food additives may potentially negatively impact anxiety-related and social behaviors and may do so via different mechanisms in males and females.

Atypical Social Development in Vasopressin-Deficient Brattleboro Rats.

Over the past 3 decades, a large body of evidence has accumulated demonstrating that the neuropeptide arginine vasopressin (AVP) plays a critical role in regulating social behavior. The overwhelming majority of this evidence comes from adults, leaving a gap in our understanding of the role of AVP during development. Here, we investigated the effect of chronic AVP deficiency on a suite of juvenile social behaviors using Brattleboro rats, which lack AVP due to a mutation in the Avp gene. Social play behavior, huddling, social investigation & allogrooming, and ultrasonic vocalizations (USVs) of male and female rats homozygous for the Brattleboro mutation (Hom) were compared with their wild-type (WT) and heterozygous (Het) littermates during same-sex, same-genotype social interactions. Male and female Hom juveniles exhibited less social play than their Het and WT littermates throughout the rise, peak, and decline of the developmental profile of play. Hom juveniles also emitted fewer prosocial 50 kHz USVs, and spectrotemporal characteristics (call frequency and call duration) of individual call types differed from those of WT and Het juveniles. However, huddling behavior was increased in Hom juveniles, and social investigation and 22 kHz USVs did not differ across genotypes, demonstrating that not all social interactions were affected in the same manner. Collectively, these data suggest that the Avp gene plays a critical role in juvenile social development.

Sensitive periods for hormonal programming of the brain.

During sensitive periods, information from the external and internal environment that occurs during particular phases of development is relayed to the brain to program neural development. Hormones play a central role in this process. In this review, we first discuss sexual differentiation of the brain as an example of hormonal programming. Using sexual differentiation, we define sensitive periods, review cellular and molecular processes that can explain their restricted temporal window, and discuss challenges in determining the precise timing of the temporal window. We then briefly review programming effects of other hormonal systems and discuss how programming of these systems interact with sexual differentiation.