Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice.

Basolateral amygdala (BLA) is a key hub for affect in the brain, and dysfunction within this area contributes to a host of psychiatric disorders. BLA is extensively and reciprocally interconnected with frontal cortex, and some aspects of its function are evolutionarily conserved across rodents, anthropoid primates, and humans. Neuron density in BLA is substantially lower in primates compared to murine rodents, and frontal cortex (FC) is dramatically expanded in primates, particularly the more anterior granular and dysgranular areas.

The mouse dorsal peduncular cortex encodes fear memory.

The rodent medial prefrontal cortex (mPFC) is functionally organized across the dorsoventral axis, where dorsal and ventral subregions promote and suppress fear, respectively. As the ventral-most subregion, the dorsal peduncular cortex (DP) is hypothesized to function in fear suppression. However, this role has not been explicitly tested.

Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice.

The basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens are similarly organized in mice and macaques, BLA-FC connections differ.

Single basolateral amygdala neurons in macaques exhibit distinct connectional motifs with frontal cortex.

Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and decision making. While it is appreciated that single BLA neurons branch and project to multiple areas in frontal cortex, the organization and frequency of this branching has yet to be fully characterized. Here, we determined the projection patterns of more than 3,000 macaque BLA neurons.

The mouse dorsal peduncular cortex encodes fear memory.

The rodent medial prefrontal cortex (mPFC) is a locus for both the promotion and suppression (e.g. extinction) of fear and is composed of four anatomically distinct subregions, including anterior cingulate 1 (Cg1), prelimbic (PL), infralimbic (IL), and the dorsal peduncular (DP) cortex.

High-throughput sequencing of macaque basolateral amygdala projections reveals dissociable connectional motifs with frontal cortex.

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for optimal emotional responding and decision-making. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here, we use MAPseq to determine the projection patterns of over 3000 macaque BLA neurons.

Ensemble-specific deficit in neuronal intrinsic excitability in aged mice.

With the prevalence of age-related cognitive deficits on the rise, it is essential to identify cellular and circuit alterations that contribute to age-related memory impairment. Increased intrinsic neuronal excitability after learning is important for memory consolidation, and changes to this process could underlie memory impairment in old age. Some studies find age-related deficits in hippocampal neuronal excitability that correlate with memory impairment but others do not, possibly due to selective changes only in activated neural ensembles.

Control of fear by discrete prefrontal GABAergic populations encoding valence-specific information.

Neurons activated by learning have been ascribed the unique potential to encode memory, but the functional contribution of discrete cell types remains poorly understood. In particular, it is unclear whether learning engages specific GABAergic interneurons and, if so, whether they differ functionally from interneurons recruited by other experiences. Here, we show that fear conditioning activates a heterogeneous neuronal population in the medial prefrontal cortex (mPFC) that is largely comprised of somatostatin-expressing interneurons (SST-INs).

GABAergic basal forebrain projections to the periaqueductal gray promote food consumption, reward and predation.

Behaviors central to the procurement and consumption of food are among those most fundamental to survival, but their inappropriate expression can lead to overeating and obesity. Nevertheless, we have a poor understanding of circuits that promote feeding independent of physiological demand. Here we demonstrate that activation of basal forebrain (BF) GABAergic neurons results in consumption of food as well as non-food items in well-fed mice, and performance of fictive eating in the absence of ingestible materials.

GABAergic microcircuitry of fear memory encoding.

The paradigm of fear conditioning is largely responsible for our current understanding of how memories are encoded at the cellular level. Its most fundamental underlying mechanism is considered to be plasticity of synaptic connections between excitatory projection neurons (PNs). However, recent studies suggest that while PNs execute critical memory functions, their activity at key stages of learning and recall is extensively orchestrated by a diverse array of GABAergic interneurons (INs).

Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice.

Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood.

The role of intrinsic excitability in the evolution of memory: Significance in memory allocation, consolidation, and updating.

Memory is a dynamic process that is continuously regulated by both synaptic and intrinsic neural mechanisms. While numerous studies have shown that synaptic plasticity is important in various types and phases of learning and memory, neuronal intrinsic excitability has received relatively less attention, especially regarding the dynamic nature of memory. In this review, we present evidence demonstrating the importance of intrinsic excitability in memory allocation, consolidation, and updating.

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts.

Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse.

Prefrontal somatostatin interneurons encode fear memory.

Theories stipulate that memories are encoded within networks of cortical projection neurons. Conversely, GABAergic interneurons are thought to function primarily to inhibit projection neurons and thereby impose network gain control, an important but purely modulatory role. Here we show in male mice that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex somatostatin (SST) interneurons and that activation of these cells controls both memory encoding and expression.

Prazosin during fear conditioning facilitates subsequent extinction in male C57Bl/6N mice.

Rationale: Recovery from a traumatic experience requires extinction of cue-based fear responses, a process that is impaired in post-traumatic stress disorder. While studies suggest a link between fear behavioral flexibility and noradrenaline signaling, the role of specific receptors and brain regions in these effects is unclear.

Objectives: Here, we examine the role of prazosin, an α1-adrenergic receptor (α1-AR) antagonist, in auditory fear conditioning and extinction.

GABAergic interneurons: The orchestra or the conductor in fear learning and memory?

Fear conditioning is a form of associative learning that is fundamental to survival and involves potentiation of activity in excitatory projection neurons (PNs). Current models stipulate that the mechanisms underlying this process involve plasticity of PN synapses, which exhibit strengthening in response to fear conditioning. However, excitatory PNs are extensively modulated by a diverse array of GABAergic interneurons whose contributions to acquisition, storage, and expression of fear memory remain poorly understood.

Prazosin during threat discrimination boosts memory of the safe stimulus.

The α-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human participants. Prazosin did not affect threat conditioning but augmented stimulus discrimination during extinction and reextinction, via lower responding to the safe stimulus.

The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning.

Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds.

Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice.

Multimodal and Site-Specific Plasticity of Amygdala Parvalbumin Interneurons after Fear Learning.

Stimulus processing in fear conditioning is constrained by parvalbumin interneurons (PV-INs) through inhibition of principal excitatory neurons. However, the contributions of PV-IN microcircuits to input gating and long-term plasticity in the fear system remain unknown. Here we interrogate synaptic connections between afferent pathways, PV-INs, and principal excitatory neurons in the basolateral amygdala.

New Learning and Unlearning: Strangers or Accomplices in Threat Memory Attenuation?

To achieve greatest efficacy, therapies for attenuating fear and anxiety should preclude the re-emergence of emotional responses. Of relevance to this aim, preclinical models of threat memory reduction are considered to engage one of two discrete neural processes: either establishment of a new behavioral response that competes with, and thereby temporarily interferes with the expression of, threat memory (new learning) or one that modifies and thereby disrupts threat memory (unlearning). We contend that a strict dichotomy of new learning and unlearning does not provide a compelling explanation for current data.

Prefrontal-amygdala fear networks come into focus.

The ability to form associations between aversive threats and their predictors is fundamental to survival. However, fear and anxiety in excess are detrimental and are a hallmark of psychiatric diseases such as post-traumatic stress disorder (PTSD). PTSD symptomatology includes persistent and intrusive thoughts of an experienced trauma, suggesting an inability to downregulate fear when a corresponding threat has subsided.