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, 475 (7356), 377-80

Excitatory Transmission From the Amygdala to Nucleus Accumbens Facilitates Reward Seeking


Excitatory Transmission From the Amygdala to Nucleus Accumbens Facilitates Reward Seeking

Garret D Stuber et al. Nature.


The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence. The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours, but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours.


Figure 1
Figure 1. Expression of ChR2-EYFP in BLA neurons and fibers projecting to the NAc
a, Red fluorescent Nissl stained coronal brain slice showing expression of ChR2-EYFP (green) following virus injection in the BLA. b, Example traces and average data of current-clamped ChR2-expressing BLA neurons action potentials in response to 5-ms light pulses(n = 7 cells, P = 0.015). c, Expression of ChR2-EYFP in the NAc following virus injection in the BLA. d, EPSCs recorded from NAc neurons following optical stimulation of BLA-to-NAc fibers before and after bath application of ­CNQX (P = 0.007; n = 4 cells). All error bars for all figures correspond to the S.E.M.
Figure 2
Figure 2. In vivo optical activation of BLA-to-NAc fibers promotes self-stimulation
a, Example cumulative activity graphs from the first behavioral session of active nosepokes made to obtain optical stimulation of BLA-to-NAc fibers in a ChR2-EYFP-expressing and a control mouse. b, Average nosepokes during the first optical self-stimulation session. (n = 12 ChR2-EYFP mice; n = 10 EYFP mice; P < 0.0001). c, Example cumulative activity graphs of nosepokes for optical stimulation following unilateral intra-NAc microinjections. d, Average nosepokes following intra-NAc microinjections (n = 19 saline; n = 11 SCH23390; n = 20 Raclopride, P = 0.0016). e, Example cumulative activity graphs of active nosepokes made for optical stimulation in mice that received intra-BLA vehicle or lidocaine. f, Average nosepokes following intra-BLA vehicle or lidocaine (n = 6 intra-BLA saline group; n = 6 intra-BLA lidocaine, P = 0.88.)
Figure 3
Figure 3. In vivo optical inactivation of BLA-to-NAc fibers reduces behavioral responding for sucrose
a, +100 pA current injection for 200 ms into NpHR expressing neurons in the BLA resulted in reliable spiking of BLA neurons (6.6 ± 0.9 spikes). In all neurons, NpHR-mediated hyperpolarization completely blocked spikes due to the current injection (P = 0.02, n = 3). b, ChR2 (473 nm) evoked EPSCs at BLA-to-NAc synapses are reduced when NpHR is activated (593.5 nm) in the same pathway. c, Average normalized lick rates (z-score) time-locked to cue onset (t = 0 – 5 s, green bar) and sucrose delivery (t = 5 s) for NpHR-and EYFP-expressing mice. BLA-to-NAc fibers were transiently inactivated (from t = −0.2 – 5.2 s) in NpHR-expressing mice on each trial of each conditioning session. d,e, Data from c broken into time bins corresponding to the cue period (t = 0 – 5 s) or the sucrose consumption period (t = 5 – 15 s). Lick rates were significantly attenuated during the cue period (e) in mice receiving BLA-to-NAc inhibition (P = 0.013 for treatment, n = 7 mice per group). Lick rates were also significantly reduced during the sucrose consumption period (f) (P = 0.001 for treatment, n = 7 mice per group).
Figure 4
Figure 4. In vivo optical activation of mPFC-to-NAc fibers does not promote self-stimulation
a, Expression of ChR2-EYFP (green) following virus injection in the mPFC. b, Expression of ChR2-EYFP in fibers originating in the mPFC and innervating the NAc. c, Average nosepokes made by mice expressing ChR2-EYFP in mPFC-to-NAc fibers and controls (ChR2-EYFP n = 12 mice; EYFP n = 10 mice; P = 0.333). d, EPSCs recorded from NAc neurons evoked by either mPFC or BLA-to-NAc optical stimulation at increasing light intensities (n = 7 cells per group, effect for stimulated input: P = 0.003).

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