2010 — 2012 |
Carter, Adam George |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dendritic Physiology and Calcium Signaling in Pyramidal Neurons of the Prefrontal
DESCRIPTION (provided by applicant): The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. Pyramidal neurons are the principal cells of the prefrontal cortex and integrate glutamatergic inputs from multiple brain regions. These excitatory neurons also receive extensive dopaminergic inputs from sub-cortical brain areas that modulate pyramidal neurons. Together, glutamatergic and dopaminergic inputs help to govern the physiological properties of pyramidal neurons and determine the function of the prefrontal cortex. The primary goal of this study is to understand how these inputs interact at the sub-cellular level in pyramidal neurons. A mechanistic approach will reveal the electrical and calcium (Ca) signals generated during synaptic transmission and integration. Ca signals control the induction of synaptic plasticity, gene expression and morphological stability of these neurons. A combination of 2-photon microscopy and 2-photon laser uncaging will be used to study these signals at individual dendrites and spines. The planned experiments will reveal the importance of different voltage-sensitive ion channels and glutamate receptors in generating Ca signals. Moreover, they will determine how dopamine receptor activation modulates these channels and receptors to influence local Ca signals. The results from these experiments will answer fundamental questions about how prefrontal pyramidal neurons integrate their synaptic inputs. Moreover, they will identify novel therapeutic targets for the debilitating neurological diseases that arise from dysfunction of these neurons. PUBLIC HEALTH RELEVANCE: The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from mice to humans. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. The proposed experiments will determine how these neurons function and identify novel treatments for these and other debilitating neurological diseases.
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2013 — 2021 |
Carter, Adam George |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synaptic and Dendritic Physiology in the Prefrontal Cortex
DESCRIPTION (provided by applicant): The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neuropsychiatric diseases, including schizophrenia and depression. Pyramidal neurons are the principal cells of the prefrontal cortex, and process diverse excitatory and inhibitory synaptic inputs. These neurons also receive extensive dopaminergic inputs from subcortical regions that modulate intrinsic and synaptic physiology. Dopamine activates metabotropic D1 receptors to enhance pyramidal neuron firing and support cognitive functions like working memory. However, previous studies have found heterogeneous effects of D1 receptors on excitatory and inhibitory responses at pyramidal neurons. We recently discovered that D1 receptors are selectively expressed in only a subpopulation of layer 5 pyramidal neurons (D1+ neurons). These neurons have compact dendrites, high input resistance, minimal h-current and pronounced burst firing compared to their D1- neighbors. Importantly, they are also selectively modulated by D1 receptors, which signal through the protein kinase A (PKA) pathway to boost excitability. The goal of this proposal is to assess how D1 receptors modulate excitatory and inhibitory responses at D1+ neurons in the mouse PFC. We first characterize the different excitatory inputs onto D1+ neurons, using a powerful combination of whole-cell recordings, optogenetics and two-photon microscopy. We then use these approaches to assess the properties of inhibitory inputs onto D1+ neurons, which derive from a variety of GABAergic interneurons. In both cases, we examine the mechanisms that underlie differential synaptic responses at D1+ neurons and their D1-neighbors. Having defined these connections, we test our hypothesis that D1 receptors regulate excitatory and inhibitory synapses only at D1+ neurons. The proposed experiments will reveal how this subpopulation of pyramidal neurons interacts with their long-range and local circuits. The results from these experiments will answer fundamental questions about dopamine regulation of cellular and synaptic physiology. They will also help to identify novel therapeutic targets for the many neuropsychiatric diseases that arise from disrupted dopamine modulation in the PFC.
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2014 — 2018 |
Carter, Adam George |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Impact of Drugs of Abuse On Striatal Circuits
DESCRIPTION (provided by applicant): The Nucleus Accumbens (NAc) is important for the learning and expression of reward-related behaviors, and strongly influenced by drugs of abuse. Medium spiny neurons (MSNs) are the principal cells of the NAc, and are commonly segregated into two distinct populations. MSNs expressing D1 dopamine receptors project directly to the midbrain (D1-MSNs), while MSNs expressing D2 dopamine receptors project indirectly via the ventral pallidum (D2-MSNs). D1-MSNs and D2-MSNs process long-range excitatory inputs from the prefrontal cortex, thalamus, ventral hippocampus and basolateral amygdala. Recent findings from our laboratory indicate that synaptic connectivity in the NAc is both cell-type and input-specific, with hippocampal inputs stronger at D1-MSNs, and other long-range inputs largely unbiased. Glutamatergic inputs ultimately synapse onto spines, the small membrane protrusions found throughout the dendrites of D1-MSNs and D2-MSNs. Each spine receives a single synaptic contact, and possesses the machinery for postsynaptic transmission, including both AMPA and NMDA receptors. The types and locations of targeted spines dictate postsynaptic responses, with inputs onto smaller or distal spines evoking weaker signals. Recent studies from our laboratory, using a novel combination of two-photon microscopy and optogenetics, reveal that subcellular connectivity is also cell-type and input-specific. Thus, hippocampal inputs selectively contact larger, proximal spines at D1-MSNs, whereas other long-range inputs show limited preference. Cocaine and other drugs of abuse are well known to have dramatic effects on both the morphological and physiological properties of MSNs in the NAc. Cocaine sensitization is a hyper-responsiveness to repeated cocaine exposure, and promotes the growth of new spines and formation of new synapses. These classical observations suggest a rearrangement of functional circuits, but the types of long-range excitatory inputs that are impacted remain unknown. New preliminary data from our lab indicates that repeated cocaine exposure triggers dramatic changes to cell-type and input-specific synaptic connectivity. Our proposed experiments will characterize how cocaine sensitization impacts the synaptic organization of the NAc at the levels of neurons, dendrites and spines. This work involves a powerful combination of whole-cell recordings, optogenetics, two-photon microscopy, two-photon uncaging, in vivo pharmacology and in vivo pharmacogenetics. Our long-term goal is to further our understanding of how cocaine and other drugs of abuse reorganize striatal circuits during the transition to drug addiction.
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