Cortical Control of Affective Networks

Abstract

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.

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

“…Prefrontal cortex engagement has been shown to be critically involved in social behaviors in humans (e.g. Dichter et al, 2009;Ho et al, 2012), and in animal models (Avale et al, 2011;Covington et al, 2010Stack et al, 2010; but see Kumar et al, 2013). In the latter, prefrontal cortex damage, whether widespread (Gonzalez et al, 2000;Shah and Treit, 2003) or localized to the prelimbic cortex (Avale et al, 2011), has been reported to increase social exploration.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…One hypothesis for how gamma oscillations might induce a change in behavioral state is through an activity-dependent strengthening of abnormally weakened excitatory synaptic networks, particularly those associated with reward and affect regulation [124]. Acute rhythmic optogenetic activation of the PFC, in the absence of any pharmacological manipulation, exerts an acute antidepressant-like effect in the forced swim test in mice [257] and sustained ketamine-like antidepressant response in the forced swim test 24-h after stimulation in rats [258]. These findings suggest that monitoring EEG activity may be of use to predict novel rapid antidepressant compounds and which patients are likely to respond to this treatment.…”

Antidepressant-like Effects of Cortical Deep Brain Stimulation Coincide With Pro-neuroplastic Adaptations of Serotonin Systems

“…Neuroanatomical tracing studies in rodents and primates indicate that the Dorsal Raphe Nucleus (DRN) receives projections from the vmPFC (8-11) and several preclinical studies have reported robust and immediate increases in DRN neural activity and serotonin output upon electrical or optogenetic stimulation of the vmPFC (6,9,10,12-14). Whether and how chronic regimens of vmPFC DBS induce neuroplasticity in the 5-HT system is not known.…”