The current study demonstrates that stressful experiences induces a negative affective state characterized by anhedonia and behavioral despair. This phenotype can be reversed independently by depotentiating observed increased synaptic strength of limbic ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the NAc shell, or restoring depression-induced decreased potassium channel function in hyperexcitable D1-MSNs. Furthermore, in nave animals, mimicking the aforementioned synaptic and intrinsic adaptations in NAc D1-MSNs induced by stressful experiences is sufficient to promote both anhedonia and behavioral despair. Moreover, utilizing a novel disconnection procedure, we demonstrate that strengthening of VH synapses and excitability changes in D1-MSNs induced by potassium channel dysfunction are serial processes that promote anhedonia and behavioral despair after stressful experiences. Lastly, we deconstruct how information gets received from the VH to NAc D1-MSNs and relayed to their downstream targets to drive negative affect. Taken together, our study identifies a novel disynaptic pathway for control of emotional behavior in which VH shapes information flow into NAc D1-MSNs to specific downstream targets. Over the last two to three decades, the dogma in the field of neuroscience is that D1-MSN activity supports appetitive and reinforcing behaviors, due to limited investigation of this cell type in negative affective states. However, here we provide unexpected, novel evidence that D1-MSNs also participate in the context of negative affective states. This evidence will encourage the field of biological psychiatry to revisit and reinterpret much of the present literature and help guide future studies. In conclusion, there is a paucity of effective treatments in the clinic for negative affective states due to a critical knowledge gap in our understanding of the mechanisms promoting such symptoms. Thus, our study provides novel, druggable targets for rationale, evidence-based therapeutic interventions for endophenotypes observed in a plethora of neuropsychiatric disorders.
| Tejeda, Hugo A; Wu, Jocelyn; Kornspun, Alana R et al. (2017) Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity. Neuron 93:147-163 |
