Interactions between the thalamus and prefrontal cortex (PFC) are important for cognitive function in animals ranging from rodents to primates. The importance of these long-range networks is highlighted by multiple neuropsychiatric diseases, including schizophrenia and ADHD. However, most of what we know about thalamo-cortical circuits comes from sensory systems, where primary thalamic inputs arrive in layer 4 (L4). In contrast, the mouse PFC is an agranular area that lacks L4, and instead receives higher-order thalamic inputs directly to superficial layers. We recently discovered that the PFC makes reciprocal connections with both the mediodorsal (MD) and ventromedial (VM) thalamus. These thalamic nuclei support distinct behaviors, but the cellular, synaptic and circuit mechanisms for their interactions with PFC are poorly understood. We found MD strongly drives layer 2/3 (L2/3) pyramidal cells, whereas VM inputs contact the dendrites of a subset of L5 pyramidal cells. Interestingly, both inputs also robustly engage inhibitory networks to drive local inhibition mediated by GABAergic interneurons. The goal of this proposal is to assess how thalamic inputs engage different populations of superficial interneurons to mediate inhibition in the PFC.
In Specific Aim 1, we use optogenetics and electrophysiology to study how thalamic inputs drive multiple classes of interneurons in superficial layers. Our preliminary data suggests that MD and VM engage complementary populations of interneurons located in different sub-layers.
In Specific Aim 2, we then use conditional optogenetics to study how these interneurons contact excitatory and inhibitory cells within and across layers. Our preliminary data indicate that the interneurons contacted by MD and VM participate in distinct inhibitory and disinhibitory circuits across multiple layers. Lastly, in Specific Aim 3, we combine 1-photon optogenetics with 2-photon microscopy to study how specific populations of interneurons mediate the suppression of dendritic Ca2+ spikes. Our preliminary data reveal that a sub-population of superficial interneurons mediates robust feed-forward inhibition in the dendrites. Together, the results from our experiments will answer fundamental questions about the organization of thalamo-cortical circuits and interneurons in the PFC. They will also help identify potential therapeutic targets for the many neuropsychiatric disorders that arise from disrupted circuitry within the PFC.

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Our goal is to determine how higher-order thalamus interacts with different populations of GABAergic interneurons to mediate inhibition in the mouse prefrontal cortex (PFC). Using a combination of electrophysiology, optogenetics and 2-photon microscopy, we will examine how two thalamic inputs interact with a variety of interneurons, how these cells synapse onto other excitatory and inhibitory cells, and how a subset of interneurons contacts the dendrites to inhibit local Ca2+ signaling. Our experiments will help elucidate how the thalamus interacts with the PFC to support cognitive function and how this may go awry in mental health disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1)
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Nadler, Laurie S
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New York University
Schools of Arts and Sciences
New York
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Liu, Xingchen; Carter, Adam G (2018) Ventral Hippocampal Inputs Preferentially Drive Corticocortical Neurons in the Infralimbic Prefrontal Cortex. J Neurosci 38:7351-7363
Anastasiades, Paul G; Marlin, Joseph J; Carter, Adam G (2018) Cell-Type Specificity of Callosally Evoked Excitation and Feedforward Inhibition in the Prefrontal Cortex. Cell Rep 22:679-692
McGarry, Laura M; Carter, Adam G (2017) Prefrontal Cortex Drives Distinct Projection Neurons in the Basolateral Amygdala. Cell Rep 21:1426-1433
McGarry, Laura M; Carter, Adam G (2016) Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex. J Neurosci 36:9391-406
Seong, Hannah J; Behnia, Rudy; Carter, Adam G (2014) Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex. J Neurophysiol 111:1960-72
Marlin, Joseph J; Carter, Adam G (2014) GABA-A receptor inhibition of local calcium signaling in spines and dendrites. J Neurosci 34:15898-911
Little, Justin P; Carter, Adam G (2013) Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. J Neurosci 33:15333-42
Seong, Hannah J; Carter, Adam G (2012) D1 receptor modulation of action potential firing in a subpopulation of layer 5 pyramidal neurons in the prefrontal cortex. J Neurosci 32:10516-21
Little, Justin P; Carter, Adam G (2012) Subcellular synaptic connectivity of layer 2 pyramidal neurons in the medial prefrontal cortex. J Neurosci 32:12808-19
Chalifoux, Jason R; Carter, Adam G (2011) Glutamate spillover promotes the generation of NMDA spikes. J Neurosci 31:16435-46

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