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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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Opposite changes in AMPAR/NMDAR following fear or reward conditioning in BLA neurons projecting to NAc or CeMa, After injecting retrobeads into NAc or CeM, animals underwent either fear or reward conditioning. b, Confocal image of retrobead labeled BLA neurons, with schematic of stimulation and recording sites (left); region in white square is enlarged (right). DAPI is shown in blue. c–f, One-way ANOVAs were performed on AMPAR/NMDAR ratios after conditioning. Open circles reflect individual data points, number of neurons are shown in each bar and representative traces for each group are below the bar. Results show mean and s.e.m. c, AMPAR/NMDAR ratio was related to training condition during fear conditioning (F2,33=5.844, **P=0.0070) and significantly lower in the Paired group relative to the Unpaired group (t31=2.21, *P<0.05). d, AMPAR/NMDAR ratio was related to training condition during reward conditioning (F2,31= 6.53, **P=0.0046) and Learners showed a greater AMPAR/NMDAR ratio than mice in the Unpaired group (t29=3.20, **P<0.01). e, In CeM projectors, AMPAR/NMDAR ratio was related to fear conditioning (F2,29=8.72, **P=0.0012) and was greater in the Paired group relative to the Unpaired group (t27=3.99, ***P<0.001). f, In CeM projectors, AMPAR/NMDAR ratio was altered by reward learning (F2,32= 3.63, *P=0.039), and was greater in Learners relative to the Unpaired group (t30=2.57, *P<0.05). g, Proposed model, arrow thickness represents relative synaptic strength.
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Figure 10: Opposite changes in AMPAR/NMDAR following fear or reward conditioning in BLA neurons projecting to NAc or CeMa, After injecting retrobeads into NAc or CeM, animals underwent either fear or reward conditioning. b, Confocal image of retrobead labeled BLA neurons, with schematic of stimulation and recording sites (left); region in white square is enlarged (right). DAPI is shown in blue. c–f, One-way ANOVAs were performed on AMPAR/NMDAR ratios after conditioning. Open circles reflect individual data points, number of neurons are shown in each bar and representative traces for each group are below the bar. Results show mean and s.e.m. c, AMPAR/NMDAR ratio was related to training condition during fear conditioning (F2,33=5.844, **P=0.0070) and significantly lower in the Paired group relative to the Unpaired group (t31=2.21, *P<0.05). d, AMPAR/NMDAR ratio was related to training condition during reward conditioning (F2,31= 6.53, **P=0.0046) and Learners showed a greater AMPAR/NMDAR ratio than mice in the Unpaired group (t29=3.20, **P<0.01). e, In CeM projectors, AMPAR/NMDAR ratio was related to fear conditioning (F2,29=8.72, **P=0.0012) and was greater in the Paired group relative to the Unpaired group (t27=3.99, ***P<0.001). f, In CeM projectors, AMPAR/NMDAR ratio was altered by reward learning (F2,32= 3.63, *P=0.039), and was greater in Learners relative to the Unpaired group (t30=2.57, *P<0.05). g, Proposed model, arrow thickness represents relative synaptic strength.

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)

Opposite changes in AMPAR/NMDAR following fear or reward conditioning in BLA neurons projecting to NAc or CeMa, After injecting retrobeads into NAc or CeM, animals underwent either fear or reward conditioning. b, Confocal image of retrobead labeled BLA neurons, with schematic of stimulation and recording sites (left); region in white square is enlarged (right). DAPI is shown in blue. c–f, One-way ANOVAs were performed on AMPAR/NMDAR ratios after conditioning. Open circles reflect individual data points, number of neurons are shown in each bar and representative traces for each group are below the bar. Results show mean and s.e.m. c, AMPAR/NMDAR ratio was related to training condition during fear conditioning (F2,33=5.844, **P=0.0070) and significantly lower in the Paired group relative to the Unpaired group (t31=2.21, *P<0.05). d, AMPAR/NMDAR ratio was related to training condition during reward conditioning (F2,31= 6.53, **P=0.0046) and Learners showed a greater AMPAR/NMDAR ratio than mice in the Unpaired group (t29=3.20, **P<0.01). e, In CeM projectors, AMPAR/NMDAR ratio was related to fear conditioning (F2,29=8.72, **P=0.0012) and was greater in the Paired group relative to the Unpaired group (t27=3.99, ***P<0.001). f, In CeM projectors, AMPAR/NMDAR ratio was altered by reward learning (F2,32= 3.63, *P=0.039), and was greater in Learners relative to the Unpaired group (t30=2.57, *P<0.05). g, Proposed model, arrow thickness represents relative synaptic strength.
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Figure 10: Opposite changes in AMPAR/NMDAR following fear or reward conditioning in BLA neurons projecting to NAc or CeMa, After injecting retrobeads into NAc or CeM, animals underwent either fear or reward conditioning. b, Confocal image of retrobead labeled BLA neurons, with schematic of stimulation and recording sites (left); region in white square is enlarged (right). DAPI is shown in blue. c–f, One-way ANOVAs were performed on AMPAR/NMDAR ratios after conditioning. Open circles reflect individual data points, number of neurons are shown in each bar and representative traces for each group are below the bar. Results show mean and s.e.m. c, AMPAR/NMDAR ratio was related to training condition during fear conditioning (F2,33=5.844, **P=0.0070) and significantly lower in the Paired group relative to the Unpaired group (t31=2.21, *P<0.05). d, AMPAR/NMDAR ratio was related to training condition during reward conditioning (F2,31= 6.53, **P=0.0046) and Learners showed a greater AMPAR/NMDAR ratio than mice in the Unpaired group (t29=3.20, **P<0.01). e, In CeM projectors, AMPAR/NMDAR ratio was related to fear conditioning (F2,29=8.72, **P=0.0012) and was greater in the Paired group relative to the Unpaired group (t27=3.99, ***P<0.001). f, In CeM projectors, AMPAR/NMDAR ratio was altered by reward learning (F2,32= 3.63, *P=0.039), and was greater in Learners relative to the Unpaired group (t30=2.57, *P<0.05). g, Proposed model, arrow thickness represents relative synaptic strength.
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