A few years ago, we observed that highly aggressive mice found aggressive social interaction to be rewarding and we hypothesized that this may directly drive aggressive behavior. Using circuit tracing techniques and slice electrophysiology we identified key differences in the activation of brain reward circuitry between highly aggressive mice and their non-aggressive counterparts. Tools such as circuit specific optogenetics along with in vivo imaging of neural activity in awake behaving mice have allowed us to functionally probe neural circuits that control the rewarding aspects of aggressive behavior. Our initial results show strong activation of a GABAergic projection from the basal forebrain to the lateral habenula (lHb) that controls both aggression and its rewarding properties. Ongoing studies in my lab aim to further dissect the inputs to lHb impacting aggressive behavior and to identify the discreet neural codes associated with such aggressive behavior along with the molecular mechanisms driving these effects.

My lab has made fundamental contributions to understanding how brain reward systems adapt to chronic stress and cocaine. Utilizing advanced histological techniques, whole cell electrophysiology and 2 photon glutamate uncaging at single spines, we have found that chronic stress or cocaine increases excitatory synaptic transmission within the nucleus accumbens (NAc) in a cell- and synapse-type specific manner to control depression- and addiction-like behaviors. More recently, we have investigated the role of specific presynaptic glutamatergic inputs to the NAc in meditating depression-like behavior using circuit specific optogenetics and electrophysiology. We have found that social defeat stress, a mouse model of depression, increases synaptic transmission specifically at thalamo-striatal synapses on NAc medium spiny neurons and that this is both necessary and sufficient to promote a depression-like behavioral phenotype.

We have found that the pro-inflammatory cytokine interleukin-6 (IL-6) is highly up regulated in serum from stress susceptible mice as well as patients with treatment resistant major depression. The source of IL-6 is from bone marrow derived leukocytes, which is released in response to stress and can penetrate the brain and act directly on neural circuits controlling mood and emotion. In order to study peripheral IL-6, we’ve generated bone marrow chimeric mice that lacks the IL-6 gene only in bone marrow derived leukocytes and found the mice were behaviorally resilient to social stress. We also administered systemic monoclonal antibodies to sequester IL-6 and promote resilience. Janssen Pharmaceuticals partially funded our work testing such antibody sequestration strategies, and based on the results, they have recently launched a phase II clinical trial testing the efficacy of Sirukumab, a humanized monoclonal antibody against IL-6, in treatment resistant unipolar depression. Our current investigations aim to define the precise mechanisms by which peripheral immune cells and pro-inflammatory signals impact synaptic mechanisms in brain reward regions