Cortical control of affective networks.

Transcranial magnetic stimulation and deep brain stimulation have emerged as therapeutic modalities for treatment refractory depression; however, little remains known regarding the circuitry that mediates the therapeutic effect of these approaches. Here we show that direct optogenetic stimulation of prefrontal cortex (PFC) descending projection neurons in mice engineered to express Chr2 in layer V pyramidal neurons (Thy1-Chr2 mice) models an antidepressant-like effect in mice subjected to a forced-swim test. Furthermore, we show that this PFC stimulation induces a long-lasting suppression of anxiety-like behavior (but not conditioned social avoidance) in socially stressed Thy1-Chr2 mice: an effect that is observed >10 d after the last stimulation. Finally, we use optogenetic stimulation and multicircuit recording techniques concurrently in Thy1-Chr2 mice to demonstrate that activation of cortical projection neurons entrains neural oscillatory activity and drives synchrony across limbic brain areas that regulate affect. Importantly, these neural oscillatory changes directly correlate with the temporally precise activation and suppression of limbic unit activity. Together, our findings show that the direct activation of cortical projection systems is sufficient to modulate activity across networks underlying affective regulation. They also suggest that optogenetic stimulation of cortical projection systems may serve as a viable therapeutic strategy for treating affective disorders.

A role for repressive histone methylation in cocaine-induced vulnerability to stress.

Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.