Inhibitory neurons are key regulators of cortical operations. Their dysfunction has been implicated as a major factor in many brain disorders. While recent studies indicate physiological and functional differences between specific types of inhibitory neurons, neural circuit mechanisms that give rise to these differences in cortical regions underlying cognition and executive function are not well understood. We focus our studies of inhibitory neuron circuit organization and function in the prelimbic area of medial prefrontal cortex (mPFC). This region is highly relevant to schizophrenia, autism, attention deficit disorders and others. The guiding hypothesis for this proposal is that the distinct connectivity of each type of inhibitory neurons differentially governs computationally distinct neural signal transformations in the mPFC, and that circuit connectivity differences between these cell types can be mapped to determine their specific roles in regulation of cortical network dynamics and behavioral output. Our proposed experiments will focus on the three major, non- overlapping inhibitory cell types or groups (parvalbumin-expressing, somatostatin-expressing and vasoactive intestinal peptide-expressing interneurons). A new Cre-dependent, genetically modified rabies-based tracing system will be used to map monosynaptic global circuit connections in the intact brain to these selected inhibitory neurons. To complement the anatomical rabies tracing, physiological input characterization will be accomplished by laser scanning photostimulation and channelrhodopsin (ChR2)-assisted circuit mapping. These studies will allow mapping of both local and long-range functional inputs to identified subtypes within each targeted cell group in brain slice preparations. Building on assessing input connections, we will map local functional outputs of these major inhibitory neuronal groups. Computational and behavioral analysis of the input and output circuit connections of specific inhibitory neuron types will be applied to understand how they regulate mPFC network oscillations in vivo and how they contribute to mPFC-controlled animal learning. This will be achieved by electrophysiological recordings made in parallel with behavioral performance measures with cell-type specific genetic inactivation. Together, the proposed research will generate new maps of inhibitory neuronal circuit wiring in medial prefrontal cortex, and it will broadly illuminate how inhibitory neuronal circuits regulate normal and maladaptive behaviors linked to neuropsychiatric and neurological diseases.
Diverse types of inhibitory interneurons can be crucial to prefrontal cortical function. The proposed studies should increase our mechanistic understanding of inhibitory neuronal organization and function in understudied but highly disease relevant prefrontal cortex. This will guide future studies to assess and treat circuits in the brains that are altered following disease or injury. The results of this research also will enable better therapeutic targeting of neuronal components disrupted by the relevant brain disorders.
|Sun, Yanjun; Nitz, Douglas A; Holmes, Todd C et al. (2018) Opposing and Complementary Topographic Connectivity Gradients Revealed by Quantitative Analysis of Canonical and Noncanonical Hippocampal CA1 Inputs. eNeuro 5:|
|Agarwal, Nitin; Xu, Xiangmin; Gopi, M (2018) Geometry processing of conventionally produced mouse brain slice images. J Neurosci Methods 306:45-56|
|Meyer, Jochen F; Golshani, Peyman; Smirnakis, Stelios M (2018) The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1. Front Neural Circuits 12:29|
|Lin, Xiaoxiao; Itoga, Christy A; Taha, Sharif et al. (2018) c-Fos mapping of brain regions activated by multi-modal and electric foot shock stress. Neurobiol Stress 8:92-102|
|Alachkar, A; Wang, L; Yoshimura, R et al. (2018) Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits. Mol Psychiatry 23:282-294|
|Grieco, Steven F; Holmes, Todd C; Xu, Xiangmin (2018) Neuregulin directed molecular mechanisms of visual cortical plasticity. J Comp Neurol :|
|Sanathara, Nayna M; Garau, Celia; Alachkar, Amal et al. (2018) Melanin concentrating hormone modulates oxytocin-mediated marble burying. Neuropharmacology 128:22-32|
|Chung, Amanda S; Miller, Samara M; Sun, Yanjun et al. (2017) Sexual congruency in the connectome and translatome of VTA dopamine neurons. Sci Rep 7:11120|
|Einstein, Michael C; Polack, Pierre-Olivier; Tran, Duy T et al. (2017) Visually Evoked 3-5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice. J Neurosci 37:5084-5098|
|Sun, Yanjun; Grieco, Steven F; Holmes, Todd C et al. (2017) Local and Long-Range Circuit Connections to Hilar Mossy Cells in the Dentate Gyrus. eNeuro 4:|
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