Biology subjects

Clem, R. L.

Publications and source records attributed to Clem, R. L..

6 recordsLinked to original sources

bioRxiv2023

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

Short abstractThe 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.

neuroscience↗

bioRxiv2023

Ventral hippocampal interneurons govern extinction and relapse of contextual associations

ABSTRACT/SUMMARYContextual associations are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the mechanisms underlying this competition remain largely enigmatic. Here we find the retrieval of contextual fear conditioning and extinction yield contrasting patterns of activity in prefrontal cortex and ventral hippocampus. Within ventral CA1, activation of somatostatin-expressing interneurons (SST-INs) occurs preferentially during extinction retrieval and correlates with differences in input synaptic transmission. Optogenetic manipulation of these cells but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in fear expression following extinction, and the ability of SST-INs to gate fear is specific to the context in which extinction was acquired. A similar pattern of results was obtained following reward-based extinction. These data show that ventral hippocampal SST-INs are critical for extinguishing prior associations and thereby gate relapse of both aversive and appetitive responses.

neuroscience↗

bioRxiv2023

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 cortex1-4, and amygdalo-frontal projections are critical for optimal emotional responding5 and decision- making6. 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 MAPseq7 to determine the projection patterns of over 3000 macaque BLA neurons. We found that one-third of BLA neurons have two or more distinct targets in parts of frontal cortex and of subcortical structures. Further, we reveal non-random structure within these branching patterns such that neurons with four targets are more frequently observed than those with two or three, indicative of widespread networks. Consequently, these multi-target single neurons form distinct networks within medial and ventral frontal cortex consistent with their known functions in regulating mood and decision-making. Additionally, we show that branching patterns of single neurons shape functional networks in the brain as assessed by fMRI-based functional connectivity. These results provide a neuroanatomical basis for the role of the BLA in coordinating brain-wide responses to valent stimuli8 and highlight the importance of high- resolution neuroanatomical data for understanding functional networks in the brain.

neuroscience↗

bioRxiv2021

Ensemble encoding of conditioned fear by prefrontal somatostatin interneurons

Neurons preferentially activated by learning have been ascribed the unique potential to encode memory. However, it remains unclear which genetically-defined cell types are recruited as part of such an ensemble, or what role discrete subpopulations play in behavior. Here we show that fear conditioning activates a heterogeneous neural ensemble in the medial prefrontal cortex (mPFC), comprised to a large degree of GABAergic interneurons immunoreactive for somatostatin (SST-INs). Using an intersectional genetic approach, we demonstrate that fear learning-activated SST-INs exhibit distinct circuit properties, are preferentially reactivated during memory retrieval, and mediate the expression of defensive freezing. We further show that a rewarding experience, morphine treatment, activates an orthogonal SST-IN population that exerts opposing control over fear. These results outline an important role for discrete GABAergic ensembles in fear memory encoding, and point to an unappreciated capacity for functional specialization among SST-INs.

neuroscience↗

bioRxiv2020

An adolescent sensitive period of heightened frontal top-down projection activity promotes local circuit integration and attentional behavior

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. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior.

neuroscience↗

bioRxiv2019

Prefrontal somatostatin interneurons encode fear memory

Theories stipulate that memories are encoded within networks of cortical projection neurons (PNs). Conversely, GABAergic interneurons (INs) are thought to function primarily to inhibit PNs and thereby impose network gain control, an important but purely modulatory role. However, we found that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex (mPFC) somatostatin interneurons (SST-INs), and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST- and parvalbumin (PV)-INs provides a potential circuit basis for SST-IN-evoked disinhibition of mPFC output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that rather than constrain mnemonic processing, potentiation of SST-IN activity represents an important causal mechanism for conditioned fear.

neuroscience↗