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Mott, D. D.

Publications and source records attributed to Mott, D. D..

4 recordsLinked to original sources

An amygdala-cortical circuit for encoding generalized fear memories.

Generalized learning is a fundamental process observed across species, contexts, and sensory modalities that enables animals to use past experiences to adapt to changing conditions. Evidence suggests that the prefrontal cortex (PFC) extracts general features of an experience that can be used across multiple situations. The anterior cingulate cortex (ACC), a region of the PFC, is implicated in generalized fear responses to novel contexts. However, the ACCs role in encoding contextual information is poorly understood, especially under increased threat intensity that promotes generalization. Here, we show that synaptic plasticity within the ACC and signaling from amygdala inputs during fear learning are necessary for generalized fear responses to novel encountered contexts. The ACC did not encode specific fear to the training context, suggesting this region extracts general features of a threatening experience rather than specific contextual information. Together with our previous work, our results demonstrate that generalized learning about threatening contexts is encoded, in part, within an ascending amygdala-cortical circuit, whereas descending ACC projections to the amygdala drive generalized fear responses during exposure to novel contexts. Our results further demonstrate that schematic learning can occur in the PFC after single-trial learning, a process typically attributed to learning over many repeated learning episodes.

neuroscience↗

Synaptic acetylcholine induces sharp wave ripples in the basolateral amygdala through nicotinic receptors

While the basolateral amygdala (BLA) is critical in the consolidation of emotional memories, mechanisms underlying memory consolidation in this region are not well understood. In the hippocampus, memory consolidation depends upon network signatures termed sharp wave ripples (SWR). These SWRs largely occur during states of awake rest or slow wave sleep and are inversely correlated with cholinergic tone. While high frequency cholinergic stimulation can inhibit SWRs through muscarinic acetylcholine receptors, it is unclear how nicotinic acetylcholine receptors or different cholinergic firing patterns may influence SWR generation. SWRs are also present in BLA in vivo. Interestingly, the BLA receives extremely dense cholinergic inputs, yet the relationship between acetylcholine (ACh) and BLA SWRs is unexplored. Here, using brain slice electrophysiology in male and female mice, we show that brief stimulation of ACh inputs to BLA reliably induces SWRs that resemble those that occur in the BLA in vivo. Repeated ACh-SWRs are induced with single pulse stimulation at low, but not higher frequencies. ACh-SWRs are driven by nicotinic receptors which recruit different classes of local interneurons and trigger glutamate release from external inputs. In total, our findings establish a previously undefined mechanism for SWR induction in the brain. They also challenge the previous notion of neuromodulators as purely modulatory agents gating these events but instead reveal these systems can directly instruct SWR induction with temporal precision. Further, these results intriguingly suggest a new role for the nicotinic system in emotional memory consolidation. Significance StatementSharp wave ripples represent a key network signature believed to be important in memory consolidation. These network events have been largely studied in the hippocampus and are suppressed by the basal forebrain cholinergic system. Sharp wave ripples also occur in the basolateral amygdala, a region critically involved in emotional memory consolidation. Here, we show a novel mechanism by which low frequency stimulation of synaptic acetylcholine in basolateral amygdala brain slices can reliably induce sharp wave ripples through a nicotinic receptor-mediated mechanism. These findings update the view of neuromodulatory systems in sharp wave ripple induction, moving past a purely modulatory role for these systems and instead establish a role where modulators, like acetylcholine, can directly drive SWRs with temporal precision.

neuroscience↗

Acetylcholine engages distinct amygdala microcircuits to gate internal theta rhythm

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in basolateral amygdala (BLA) underlie emotional memory, yet their mechanism remains unclear. Using brain slice electrophysiology in mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potential that depend upon activation of cholecystokinin (CCK) interneurons (INs). Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, gating BLA theta. ACh-induced theta activity is more readily evoked in BLA over cortex or hippocampus, suggesting preferential activation of BLA during high ACh states. These data reveal a SOM-CCK IN circuit in BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.

neuroscience↗

Differential regulation of prelimbic and thalamic transmission to the basolateral amygdala by acetylcholine receptors

The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity and synaptic transmission. Cholinergic signaling in BLa is thought to occur through both a slow mode of volume transmission as well as a rapid, phasic mode. However, the relative effect of each mode of signaling in BLa is not understood. Here, we used electrophysiology and optogenetics in mouse brain slices to compare regulation of afferent input from cortex and thalamus to the BLa by these two modes of transmission. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on glutamatergic transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower muscarinic receptor (mAChR)-mediated depression. In contrast, tonic elevation of ACh through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission at cortical inputs through mAChRs only. This suppression was not observed at thalamic inputs to BLa. In agreement with this pathway-specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex (PL) than thalamus. Muscarinic inhibition at PL input was dependent on presynaptic M4 mAChRs, while at thalamic input it depended upon M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that depends upon the mode of ACh release and is both pathway specific and frequency dependent. Significance statementCholinergic modulation of the basolateral amygdala regulates formation of emotional memories, but the mechanisms underlying this regulation are not well understood. Here, we show, using mouse brain slices, that ACh differentially regulates afferent transmission to the BLa depending on the mode of cholinergic signaling. Rapid, phasic ACh produces a biphasic excitatory-inhibitory regulation of glutamatergic transmission mediated by nicotinic and muscarinic receptors, respectively. In contrast, slow, tonic ACh produces muscarinic inhibition only. Tonic regulation is pathway specific with cortical input regulated more strongly than thalamic input. This disparity is caused by differential regulation by M4 and M3 receptors at the two inputs. Specific targeting of these receptors may thus provide a therapeutic strategy to bias amygdalar processing and regulate emotional memory.

neuroscience↗