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A circuit mechanism for differentiating positive and negative associations.

Namburi P, Beyeler A, Yorozu S, Calhoon GG, Halbert SA, Wichmann R, Holden SS, Mertens KL, Anahtar M, Felix-Ortiz AC, Wickersham IR, Gray JM, Tye KM - Nature (2015)

Bottom Line: Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning.We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features.Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

View Article: PubMed Central - PubMed

Affiliation: 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Neuroscience Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

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Location of BLA projectors recorded and analyzed for each experimental group of Figure 1Top, Representative DIC image showing the location of the stimulation electrode around a bundle of fibers of the internal capsule and a neuron recorded in the BLA (at the tip of the micropipette). The location of the recorded cell is indicated by an orange open circle. Scale bar reflects 200 μm. Bottom, Atlas schematics (1.5 mm × 1.5 mm) showing BLA at various antero-posterior (AP) positions relative to Bregma. Each circle represents the location of a neuron from which AMPDAR/NMDAR ratio was acquired (Figure 1). NAc projector locations are summarized in rows 1 and 2 and CeM projector locations are summarized in rows 3 and 4. Color of the circle represents the conditioning group of the animal from which AMPDAR/NMDAR ratio was acquired.
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Figure 2: Location of BLA projectors recorded and analyzed for each experimental group of Figure 1Top, Representative DIC image showing the location of the stimulation electrode around a bundle of fibers of the internal capsule and a neuron recorded in the BLA (at the tip of the micropipette). The location of the recorded cell is indicated by an orange open circle. Scale bar reflects 200 μm. Bottom, Atlas schematics (1.5 mm × 1.5 mm) showing BLA at various antero-posterior (AP) positions relative to Bregma. Each circle represents the location of a neuron from which AMPDAR/NMDAR ratio was acquired (Figure 1). NAc projector locations are summarized in rows 1 and 2 and CeM projector locations are summarized in rows 3 and 4. Color of the circle represents the conditioning group of the animal from which AMPDAR/NMDAR ratio was acquired.

Mentions: To test this, we selected the NAc and CeM as candidate target regions and examined the synaptic changes onto either NAc-projecting BLA neurons (NAc projectors) or CeM-projecting BLA neurons (CeM projectors) following fear conditioning or reward conditioning (Fig. 1). To identify the projection target of BLA neurons, we injected retrogradely-traveling fluorescent beads (retrobeads) into either the NAc or CeM to label BLA neurons sending axon terminals to these regions (Fig. 1a; Extended Data Fig. 1). After retrobead migration upstream to BLA cell bodies, we trained mice in fear or reward conditioning paradigms wherein a tone was paired with either a foot shock or sucrose delivery. Mice in reward conditioning groups were food restricted 1 day before the conditioning session to increase motivation to seek sucrose (Extended Data Fig. 1). AMPAR/NMDAR ratio, a proxy for glutamatergic synaptic strength, increases after either fear or reward conditioning in the BLA1,2,5,18. We used matched experimental parameters across groups in an acute slice preparation stimulating axons arriving via the internal capsule and performing whole-cell patch-clamp recordings in retrobead-identified NAc projectors and CeM projectors, which we observed to be topographically intermingled (Fig. 1b; Extended Data Fig. 2).


A circuit mechanism for differentiating positive and negative associations.

Namburi P, Beyeler A, Yorozu S, Calhoon GG, Halbert SA, Wichmann R, Holden SS, Mertens KL, Anahtar M, Felix-Ortiz AC, Wickersham IR, Gray JM, Tye KM - Nature (2015)

Location of BLA projectors recorded and analyzed for each experimental group of Figure 1Top, Representative DIC image showing the location of the stimulation electrode around a bundle of fibers of the internal capsule and a neuron recorded in the BLA (at the tip of the micropipette). The location of the recorded cell is indicated by an orange open circle. Scale bar reflects 200 μm. Bottom, Atlas schematics (1.5 mm × 1.5 mm) showing BLA at various antero-posterior (AP) positions relative to Bregma. Each circle represents the location of a neuron from which AMPDAR/NMDAR ratio was acquired (Figure 1). NAc projector locations are summarized in rows 1 and 2 and CeM projector locations are summarized in rows 3 and 4. Color of the circle represents the conditioning group of the animal from which AMPDAR/NMDAR ratio was acquired.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4418228&req=5

Figure 2: Location of BLA projectors recorded and analyzed for each experimental group of Figure 1Top, Representative DIC image showing the location of the stimulation electrode around a bundle of fibers of the internal capsule and a neuron recorded in the BLA (at the tip of the micropipette). The location of the recorded cell is indicated by an orange open circle. Scale bar reflects 200 μm. Bottom, Atlas schematics (1.5 mm × 1.5 mm) showing BLA at various antero-posterior (AP) positions relative to Bregma. Each circle represents the location of a neuron from which AMPDAR/NMDAR ratio was acquired (Figure 1). NAc projector locations are summarized in rows 1 and 2 and CeM projector locations are summarized in rows 3 and 4. Color of the circle represents the conditioning group of the animal from which AMPDAR/NMDAR ratio was acquired.
Mentions: To test this, we selected the NAc and CeM as candidate target regions and examined the synaptic changes onto either NAc-projecting BLA neurons (NAc projectors) or CeM-projecting BLA neurons (CeM projectors) following fear conditioning or reward conditioning (Fig. 1). To identify the projection target of BLA neurons, we injected retrogradely-traveling fluorescent beads (retrobeads) into either the NAc or CeM to label BLA neurons sending axon terminals to these regions (Fig. 1a; Extended Data Fig. 1). After retrobead migration upstream to BLA cell bodies, we trained mice in fear or reward conditioning paradigms wherein a tone was paired with either a foot shock or sucrose delivery. Mice in reward conditioning groups were food restricted 1 day before the conditioning session to increase motivation to seek sucrose (Extended Data Fig. 1). AMPAR/NMDAR ratio, a proxy for glutamatergic synaptic strength, increases after either fear or reward conditioning in the BLA1,2,5,18. We used matched experimental parameters across groups in an acute slice preparation stimulating axons arriving via the internal capsule and performing whole-cell patch-clamp recordings in retrobead-identified NAc projectors and CeM projectors, which we observed to be topographically intermingled (Fig. 1b; Extended Data Fig. 2).

Bottom Line: Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning.We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features.Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

View Article: PubMed Central - PubMed

Affiliation: 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Neuroscience Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.

Show MeSH
Related in: MedlinePlus