Project description:The basolateral amygdala (BLA) contains discrete neuronal circuits that integrate positive or negative emotional information and drive the appropriate innate and learned behaviors. Whether how these circuits consist of genetically-identifiable and anatomically segregated neuron types, is currently poorly understood. Also, our understanding of the response patterns and behavioral spectra of genetically-identifiable BLA neurons is limited. Here, we classified 11 glutamatergic BLA cell types having topography in BLA. Several clusters were enriched in lateral versus basal amygdala, others were enriched in either anterior or posterior regions of the BLA. Two of these BLA subpopulations innately responded to valence-specific stimuli, whereas one represented to both aversive and social cues. Positive-valence BLA neurons promoted normal feeding, while mixed selectivity neurons promoted fear learning and social interactions. These findings enhance our understanding of cell type diversity and spatial organization of the BLA and the role of distinct BLA populations in representing valence-specific and mixed stimuli.
Project description:Activity-dependent transcriptional profiling was performed in the basolateral amygdala in order to identify unique genetic markers for functionally distinct neuronal populations
Project description:A substantial proportion of basal amygdala (BA) glutamate neurons project to nucleus accumbens (NAc). The evidence that these neurons are activated by reward and/or aversion is equivocal. Social stimuli are highly salient, and in male mice we conducted a detailed analysis of the responsiveness of BA-NAc neurons to estrous female (social reward, SR) or aggressive male (social aversion, SA). Both SR and SA activated c-Fos expression in a relatively high number of BA-NAc neurons in intermediate (int) BA. Using Fos-TRAP2 mice, the majority of social int-BA-NAc neurons were activated by either SR or SA, i.e. were monovalent, and in similar numbers. Fiber photometry provided corroborative evidence that int-BA-NAc neural pathway activity was similar in response to SR or SA. These findings contribute substantially to understanding the topography and valence-specificity of BA-NAc neurons with respect to highly salient stimuli, and to identifying molecular targets for treatment of reward- or aversion-specific psychopathologies.
Project description:Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach and avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.
Project description:Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala (BLA) is a center of salience networks that underlie emotional experiences and thus plays a key role in long-term fear memory formation. Here we used single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and brain-derived neurotrophic factor (BDNF) signaling, mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB) activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Strikingly, upon long-term memory formation a neuronal sub-population defined by increased Penk and decreased Tac expression constituted the most prominent component of the BLA’s memory engram.
Project description:The amygdalostriatal transition zone (ASt) is anatomically poised to provide a shortcut between corticolimbic and basal ganglia circuitry, and mediate behavioral responses to stimuli in parallel with the amygdala. Like the amygdala, the ASt receives converging sensory input from thalamic and cortical pathways. However, the projections of the ASt are distinct from canonical outputs of the amygdala complex, and are integrated with striatal circuits involved in action selection. Despite this intriguing circuit connectivity, the function of the ASt is almost completely unknown. In the present study, we collected cellular resolution recordings of genetically-defined neurons during a valence discrimination task to interrogate the functional role of ASt circuitry, and characterized the transcriptomic profile of the ASt in comparison to neighboring regions. We find that ASt neurons, and specifically, ASt neurons expressing dopamine receptor 2 (D2+), robustly encode sustained conditioned responses to cues of negative valence. Selective inhibition of D2+ ASt neurons was found to cause a striking reduction in conditioned fear responses. We also used single-nucleus RNA sequencing to generate a comprehensive profile of gene expression in ASt neurons, and found that the ASt is genetically distinct from adjacent GABAergic brain regions. RNAscope labelling also confirmed there is a greater proportion of D2+ neurons than D1+ neurons in the ASt, a unique feature compared to other regions of the striatum. Together, our findings provide the first evidence the ASt is a critical structure for encoding learned associations to direct motivated behavior.
Project description:The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Different neuronal populations of the basolateral amygdala complex (BLA) encode fearful or rewarding associations, but the molecular identity of these functionally distinct populations of BLA neurons remained unknown. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc-projectors) or the centromedial amygdala (CeM-projectors) underwent opposing synaptic changes following fear or reward conditioning. The photostimulation of NAc projectors supported positive reinforcement while photostimulation of CeM projectors mediated negative reinforcement. In search of defining molecular characteristics of these functionally-distinct BLA neuronal populations, we compared gene expression profiles of NAc- and CeM-projectors.
Project description:Basolateral excitatory neurons constitute a prominent output neuron class of the amygdala. Here, we examined diversity in this cell type using single-cell RNA-seq.
Project description:The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Different neuronal populations of the basolateral amygdala complex (BLA) encode fearful or rewarding associations, but the molecular identity of these functionally distinct populations of BLA neurons remained unknown. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc-projectors) or the centromedial amygdala (CeM-projectors) underwent opposing synaptic changes following fear or reward conditioning. The photostimulation of NAc projectors supported positive reinforcement while photostimulation of CeM projectors mediated negative reinforcement. In search of defining molecular characteristics of these functionally-distinct BLA neuronal populations, we compared gene expression profiles of NAc- and CeM-projectors. For comparison of gene expression profiles of NAc- and CeM-projectors, we conducted two independent RNA sequencing experiments. In experiment-1, a total of n=9 samples (n=4 NAc- and n=5 CeM-projectors) are analyzed. In experiment-2, a total of n=8 samples (n=4 NAc- and n=4 CeM-projectors) are analyzed.
Project description:Chronic pain is one of the most significant and costly medical problems throughout the world. Recent evidence has confirmed the hippocampus as an active modulator of pain chronicity but the underlying mechanisms remain poorly defined. By means of in vivo electrophysiology together with chemogenetic and optogenetic manipulations in freely behaving mice, we identified a neural ensemble in the ventral hippocampal CA1 (vCA1) that showed inhibitory responses to noxious external stimuli, but not to innocuous stimuli. Following peripheral inflammation, this neuronal ensemble became responsive to innocuous stimuli and causally contributed to sensory hypersensitivity in inflammatory animals. Mimicking this inhibition of vCA1 neurons using chemogenetics in naïve mice induced chronic pain-like behavioral changes, whereas activating these vCA1 neurons in mice with chronic peripheral inflammation resulted in a striking reduction of pain-related behaviors. Pathway-specific manipulation of vCA1 projections to the basolateral amygdala (BLA) and infralimbic cortex (IL) showed that these pathways were differentially involved in pain modulation at different temporal stages of chronic inflammatory pain. These results confirm a crucial role of the ventral hippocampus and its circuits in modulating the development of chronic pain in mice.