Grants and Contracts Details
Description
A significant obstacle to developing effective drug addiction therapies is that drug-induced neuronal plasticity
may be restricted to discrete neuronal populations within brain reward areas. The processes driving selection
of specific cells from a larger pool of available neurons are not clear. Our long-term goal is to identify the
mechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression of
cocaine seeking and taking. In this application, our objective is to identify cocaine-related neuronal adaptations
that depend on astrocytic signaling. We propose a hypothesis that astrocytic signals recruit discrete
subpopulations of MSNs within the nucleus accumbens (NAc) shell to facilitate neuronal and behavioral
plasticity associated with cocaine self-administration in the rat. This hypothesis is supported by our preliminary
and published data and studies from other groups. The rationale for pursuing this hypothesis is that despite a
growing recognition that astrocytes actively modulate neuronal activity, little is known about the role of
astrocytes in coordination of local circuits and even less about regulation of local circuits by cocaine. On the
basis of substantial preliminary data we will test our central hypothesis in three specific aims: 1) Characterize
the impact of astrocyte signaling on cocaine-induced NMDA receptor (NMDAR) plasticity in MSN microcircuits.
2) Characterize the impact of astrocyte signaling on cocaine-induced AMPA receptor (AMPAR) plasticity in
synchronously active MSNs. 3) Identify the consequences of astrocyte-synchronized neuronal activity on
cocaine seeking and taking. In the first aim, we will use a unique characteristic of neuronal response to
astrocyte-derived signals, slow inward currents (SICs), to test the hypothesis that cocaine-induced plasticity of
extrasynaptic NMDARs, previously linked to cocaine exposure, is restricted to NAc shell MSNs displaying SIC
events. The second aim is built on classical knowledge linking NMDAR-mediated signaling to plasticity of
synaptic AMPARs and current evidence indicating that NMDAR-mediated SICs co-occur in neuronal
subpopulations. In this aim, we will determine whether cocaine-induced plasticity of synaptic AMPAR signaling
is restricted to subpopulations of NAc shell MSNs synchronized by astrocyte-derived signals. In the third aim,
we will test the hypothesis that facilitation and inhibition of astrocyte-driven neuronal synchronization will,
respectively, facilitate and inhibit cocaine-seeking behaviors. The approach is significant because it improves
our ability to identify cell populations responsible for specific behavioral responses. This ability is critical for
targeted therapeutic approaches. Our approach is innovative because: it considers a novel hypothesis of
astroglia as active participants in selection of cocaine-relevant neuronal microcircuits, it facilitates development
of novel viral tools to identify such microcircuits, and it seeks to identify novel mechanisms of cocaine-induced
neuroglial plasticity. Completion of these studies will expand understanding of the relationship between glial
signaling, individual neuron excitability, local network function, and behavioral outcomes in the context of
cocaine addiction.
Status | Finished |
---|---|
Effective start/end date | 2/1/17 → 11/30/22 |
Funding
- National Institute on Drug Abuse: $947,578.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.