Biology subjects

Kretsge, L. N.

Publications and source records attributed to Kretsge, L. N..

3 recordsLinked to original sources

bioRxiv2020

Distinct VIP interneurons in the cingulate cortex encode anxiogenic and social stimuli

A hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas encode such diverse information. The anterior cingulate cortex (ACC), for example, is important in both emotional regulation and social cognition. Previous work shows activation of the ACC to anxiety-related and social stimuli, but it is unknown how subpopulations or microcircuits within the ACC simultaneously encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of many cells in local cortical microcircuits, but it is unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information. Using in vivo calcium imaging and miniscopes in freely behaving mice to monitor VIPACC activity, we identified distinct, non-overlapping subpopulations of VIPACC that preferentially activated to either anxiogenic, anxiolytic, social, or non-social stimuli. We determined that stimulus-selective cells encode the animals behavioral states and VIP interneuron clusters may co-activate, improving this encoding. Finally, we used trans-synaptic tracing to show that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition. These findings demonstrate not only that the ACC is not homogeneous in its function, but also that there is marked functional heterogeneity even within disinhibitory interneuron populations. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

neuroscience↗

bioRxiv2020

Ventral tegmental area GABA neurons mediate stress-induced anhedonia.

Stressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4 and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.

neuroscience↗

bioRxiv2019

Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is unknown whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia. We find evidence that microglia-neuron interactions and microglia-mediated synaptic engulfment are enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in early social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

neuroscience↗