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Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

ABSTRACT: BACKGROUND:Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned behavior. METHODS:We used Fos-GFP transgenic mice that contained a transgene with a Fos promoter driving expression of green fluorescent protein (GFP) to detect neurons that were strongly activated during associative learning, in this case, context-independent and context-specific cocaine-induced locomotor sensitization. Whole-cell electrophysiological recordings were used to assess synaptic alterations in specifically activated GFP-positive (GFP+) neurons compared with surrounding nonactivated GFP-negative (GFP-) neurons 90 min after the sensitized locomotor response. RESULTS:After context-independent cocaine sensitization, cocaine-induced locomotion was equally sensitized by repeated cocaine injections in two different sensitization contexts. Correspondingly, silent synapses in these mice were induced in GFP+ neurons, but not GFP- neurons, after sensitization in both of these contexts. After context-specific cocaine sensitization, cocaine-induced locomotion was sensitized exclusively in mice trained and tested in the same context (paired group), but not in mice that were trained in one context and then tested in a different context (unpaired group). Silent synapses increased in GFP+ neurons, but not in GFP- neurons from mice in the paired group, but not from mice in the unpaired group. CONCLUSIONS:Our results indicate that silent synapses are formed only in neuronal ensembles of the nucleus accumbens shell that are related to associative learning.

SUBMITTER: Whitaker LR

PROVIDER: S-EPMC4753139 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

Whitaker Leslie R LR Carneiro de Oliveira Paulo E PE McPherson Kylie B KB Fallon Rebecca V RV Planeta Cleopatra S CS Bonci Antonello A Hope Bruce T BT

Biological psychiatry 20150814 3

<h4>Background</h4>Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned b ...[more]

PMID: 26386479

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Project description:Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, then animals may adapt accordingly by inhibiting food-seeking responses. Sparsely activated sets of neurons, coined "neuronal ensembles," have been shown to encode the strength of reward-cue associations. Although alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice, which express green fluorescent protein (GFP) in activated neurons, after appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP- neurons. After extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell.SIGNIFICANCE STATEMENT Sparsely distributed sets of neurons called "neuronal ensembles" encode learned associations about food and cues predictive of its availability. Widespread changes in neuronal excitability have been observed in limbic brain areas after associative learning, but little is known about the excitability changes that occur specifically on neuronal ensembles that encode appetitive associations. Here, we reveal that sucrose cue exposure recruited a more excitable ensemble in the nucleus accumbens, but not orbitofrontal cortex, compared with their surrounding neurons. This excitability difference was not observed when the cue's salience was diminished after extinction learning. These novel data provide evidence that the intrinsic excitability of appetitive memory-encoding ensembles is regulated differentially across brain areas and adapts dynamically to changes in associative strength.

Dataset Information

Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

Publications

Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

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