Visualizing an emotional valence map in the limbic forebrain by TAI-FISH

Abstract

A fundamental problem in neuroscience is how emotional valences are represented in the brain. We know little about how appetitive and aversive systems interact and the extent to which information regarding these two opposite values segregate and converge. Here we used a new method, tyramide-amplified immunohistochemistry-fluorescence in situ hybridization, to simultaneously visualize the neural correlates of two stimuli of contrasting emotional valence across the limbic forebrain at single-cell resolution. We discovered characteristic patterns of interaction, segregated, convergent and intermingled, between the appetitive and aversive neural ensembles in mice. In nucleus accumbens, we identified a mosaic activation pattern by positive and negative emotional cues, and unraveled previously unappreciated functional heterogeneity in the D1- and D2-type medium-spiny neurons, which correspond to the Go and NoGo pathways. These results provide insights into the coding of emotional valence in the brain and act as a proof of principle of a powerful methodology for simultaneous functional mapping of two distinct behaviors.

Activating positive memory engrams suppresses depression-like behaviour

“…In rodents, optogenetic stimulation of mPFC neurons, mPFC to raphe projections, and VTA dopaminergic neurons achieved a rapid reversal of stress-induced maladaptive behaviors 4,11,12 .. We speculate that our acute behavioral changes reflect the degree to which directly stimulating positive memory engram-bearing cells might bypass the plasticity that normally takes antidepressants weeks or months to achieve, thereby temporarily suppressing the depression-like state. In support, we observed that the effects of optically stimulating a positive memory are contingent on active glutamatergic projections from the amygdala to the NAcc in real-time, as well as intra-NAcc dopamine activity 19 . Our data dovetail with this circuit's proposed role of relaying BLA stimulus-reward associations to a ventral striatal motor-limbic interface.…”

“…3c) of BLA neurons and simultaneous activation of ChR2-mCherry-positive DG cells, respectively, in stressed mice. At the neuronal level, light-induced reactivation of DG cells previously activated by a positive experience also reactivated BLA 8 and NAcc 19 , but not mPFC, cells (i.e. endogenous c-Fos + cells, red) previously activated by the same positive experience (i.e.…”

“…The NAC has been heavily implicated in stress responses, mood disorders, and processing natural rewards 2,5,[11][12][13][16][17][18][19][20][21] . Moreover, pathophysiological dysfunction of the NAcc in response to various stressors has been implicated in anhedonia and reward conditioning [18][19][20][21] .…”

“…Moreover, pathophysiological dysfunction of the NAcc in response to various stressors has been implicated in anhedonia and reward conditioning [18][19][20][21] . Our within-subject experiments revealed that, in the TST, the behavioral effects of optically reactivating DG cells labeled by a positive experience were blocked in the group of mice that concurrently received the glutamate receptor antagonists NBQX and AP5 in the NAcc, but not in the group that received saline, without altering basal locomotion (Extended Data Fig.…”

“…Our data dovetail with this circuit's proposed role of relaying BLA stimulus-reward associations to a ventral striatal motor-limbic interface. This interface is thought to be capable of coalescing such information with motivational states and finally translating such activity into behaviorally relevant outputs 5,[18][19][20] .…”