Social avoidance manifests across a host of psychiatric illnesses with causes ranging from disinterest in social contact to negative emotional states evoked by social encounters. While the causes of social avoidance are diverse, past social trauma can result in severe social avoidance thought to reflect reduced social reward. Despite a deep clinical understanding of social trauma and its resultant effects on social behavior, we know very little about the underlying neural circuitry involved. Preclinical social trauma models have been utilized in recent years to better understand the biological underpinnings of such changes in social behavior. For example, the CSDS model has been utilized extensively to understand how reward circuitry mediates social interaction behavior, yet very little is known regarding the underlying meaning of such behavioral deficits. In the Russo lab we’ve taken a multipronged approached by assessing molecular, cellular, and physiological alterations throughout the brain that mediate susceptibility to social stress as defined by long lasting social avoidance and reduced responses to natural rewards. In one of our recent projects, we utilized an unbiased iDisco+ approach coupled with advanced tracing methods to identify the lateral septum (LS) and its downstream targets as being highly activated in both male and female susceptible mice during avoidance of a normally rewarding social target. Functional studies with optogenetics and chemogenetics show that activation of the LS elicits social avoidance and prevents context dependent social reward by inhibiting downstream reward centers (Figure 1). Our work is providing fundamentally new insight into the neural mechanisms underlying post-stress social reward deficits.

Work from our group and others suggests that elevated peripheral immune factors, which can gain access to limbic regions of brain via stress-related breakdown of the BBB (Figure 2), may represent an important factor driving behavioral symptoms in depression. In a seminal study, we have shown that chronic social defeat stress (CSDS) in mice results in loss of the tight junction protein Claudin-5 (CLDN5) and breakdown of the endothelial barrier allowing greater entry of IL-6 directly into brain reward regions like the NAc and mPFC—although the latter is sex specific and only occurs in female mice. Similar changes in CLDN5 mRNA in postmortem human brain from MDD subjects has also been observed, providing us with early evidence to link human MDD with BBB impairments. In terms of specific symptom domains and constructs, we and others have shown that there is a strong association between the immune system and reward dysfunction, and that increased peripheral inflammation correlates with clinical measures of anhedonia. However, the fundamental mechanisms by which the peripheral immune system and BBB interact ultimately leading to behavioral changes is not well understood. Using a computational approach to filter existing bulk RNA-seq data to identify endothelial-enriched transcripts, we found many genes differentially expressed between MDD and healthy control (HC) subjects. We also found that in MDD subjects increased BBB-permeability correlates with increased anhedonia. This is further substantiated by the finding that opening of the BBB by viral-mediated downregulation of CLND5 in NAc of mice increases vulnerability to stress-induced reward dysfunction. While the pathophysiology of increased BBB permeability is not yet known, we are using rodent models, informed by clinical data, to provide an increasingly sophisticated understanding of the mechanisms facilitating immune-brain interactions in depression.

Our lab works closely with clinical parterns to identify liquid biomarkers associated with unipolar depression, post traumatic stress disorders (PTSD) and neuropsychiatric post-acute sequelae of SARS CoV-2 (pasc) infection. The overall objective of the work is to provide a rigorous characterization of body fluid-based (e.g., ‘liquid’) biosignatures of stress signatures in humans (Figure 3). Based on our ongoing and published work in rodent stress models and in humans with depression and anhedonia, we have identified three highly promising categories of liquid biosignatures: (1) inflammatory monocyte-derived factors, (2) microRNAs (miRNAs), and (3) extracellular vesicles (EVs), also known as exosomes. We use information gathered from experiments assessing each of these 3 biosignatures and use predictive modeling to predict symptoms, such as deficits on effort-based reward discounting and other behavioral measures of anhedonia (‘external features’). We are also building an integrated model based on the predictors identified, thereby moving the field closer to developing a multi-channel liquid biosignature for stress-related disorders. Since the work reflects translation into humans from completed and ongoing behavioral and molecular neuroscience studies in rodent stress models, our translational research program is aiming to define the biological basis of depression and PTSD.

Aggression is a collection of evolutionarily conserved behaviors meant to control social hierarchies and protects valuable resources like mates, food, and territory. In most cases, aggression is a necessary, adaptive component of social behavior. However, aggression towards others can be considered pathological when it threatens lives, increases risk of depression and anxiety in victims and witnesses, and incurs major economic burdens on society. While such aggressive behavior can manifest across a wide range of psychiatric and neurological diseases, there are few, if any, approved treatments aimed specifically at curbing it. Despite the massive costs of violence on society, the pervasiveness of aggression among psychiatric patients, and our current lack of treatments, aggression has been understudied, particularly in females, relative to other emotional behaviors. A growing number of preclinical studies in recent years has shed some light on a limited number of brain regions, cell types, and neural ensembles governing specific components of aggressive behavior, however, there remains significant gaps in our understanding. We take a broad approach at understanding the neural circuit mechanisms governing aggressive social encounters. By Using behavior analysis, whole brain cFos analysis, computational biology, electrophysiology and in vivo Ca²⁺ imaging, we have shown that nuclei within the ventral midbrain can encode and directly modulate the motivational or rewarding component of aggressive vs. non-aggressive social behavior in both males and females (Figure 4). We are currently extending upon this work in many important ways, including an unbiased network analysis in which we hope to identify sex specific neural circuit control over aggressive social encounters.