The complex architecture of cortical microcircuits is thought to comprise variations of canonical microcircuits that perform elemental computations. In the midst of specialized local computations, cortex also receives global input from a variety of long-range neuromodulatory centers. This proposal investigates the relationship between these two types of circuits. A recently identified cortical circuit motif is controlled by a class of interneurons defined by their expression of vasoactive intestinal polypeptide (VIP), which disinhibit pyramidal cells across four distinct cortical areas, thus defining a canonical cortical circuit. These VIP interneurons in the auditory cortex are recruited in response to reinforcement signals (reward and punishment), which are likely driven by neuromodulatory systems. Therefore the dual objectives of this proposal are to determine both the generality of VIP recruitment by reinforcement signals and the circuit mechanisms responsible for this activity. First we will evaluate the cortex-wide generality of VIP interneuron recruitment by reinforcers using a combination of sophisticated techniques for neuron identification and evaluation of their activity. Second, we will identify which inputs drive reinforcement responses in VIP neurons. We will map all common regions across the brain that provide inputs to cortical VIP neurons, with a focus on the cholinergic and serotonergic neuromodulatory systems and determine the pathway(s) causally responsible. Finally, we will determine how different subtypes of VIP neurons are recruited and driven. Completion of these aims should reveal fundamental principles of how the VIP- controlled cortical microcircuit functions cortex-wide and serves as a conduit for fast neuromodulatory control.

Public Health Relevance

This proposal aims to determine the cortex-wide generality for the behavioral function of a canonical cortical microcircuit controlled by an interneuron-targeting interneuron (VIP) and determine whether it acts as a conduit for fast neuromodulatory action. Our studies are expected reveal fundamental principles about the functional roles of a cortical microcircuit that are applicable across cortical regions and also advance a mechanistic understanding of how neuromodulatory systems can control cortex on a fast time scale.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS075531-06A1
Application #
9472752
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Gnadt, James W
Project Start
2011-07-01
Project End
2022-07-31
Budget Start
2017-09-15
Budget End
2018-07-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Neuro Cloud Consortium. Electronic address: jovo@jhu.edu; Neuro Cloud Consortium (2016) To the Cloud! A Grassroots Proposal to Accelerate Brain Science Discovery. Neuron 92:622-627
Hangya, Balázs; Ranade, Sachin P; Lorenc, Maja et al. (2015) Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback. Cell 162:1155-68
Lin, Shih-Chieh; Brown, Ritchie E; Hussain Shuler, Marshall G et al. (2015) Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition. J Neurosci 35:13896-903
Hangya, Balázs; Pi, Hyun-Jae; Kvitsiani, Duda et al. (2014) From circuit motifs to computations: mapping the behavioral repertoire of cortical interneurons. Curr Opin Neurobiol 26:117-24
Kepecs, Adam; Fishell, Gordon (2014) Interneuron cell types are fit to function. Nature 505:318-26
Sanders, Joshua I; Kepecs, Adam (2014) A low-cost programmable pulse generator for physiology and behavior. Front Neuroeng 7:43
Takada, Naoki; Pi, Hyun Jae; Sousa, Vitor H et al. (2014) A developmental cell-type switch in cortical interneurons leads to a selective defect in cortical oscillations. Nat Commun 5:5333
Kvitsiani, D; Ranade, S; Hangya, B et al. (2013) Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498:363-6
Ranade, Sachin; Hangya, Balazs; Kepecs, Adam (2013) Multiple modes of phase locking between sniffing and whisking during active exploration. J Neurosci 33:8250-6
Pi, Hyun-Jae; Hangya, Balázs; Kvitsiani, Duda et al. (2013) Cortical interneurons that specialize in disinhibitory control. Nature 503:521-4