Basal forebrain cholinergic signalling: development, connectivity and roles in cognition

Impairment in acquisition of conditioned fear in schizophrenia

Animals must learn to predict varying threats in the environment to survive by enacting defensive behaviors. Dopamine is involved in the prediction of rewards, encoding a reward prediction error in a similar manner to temporal difference learning algorithm. However, the corresponding molecular and computational form of threat prediction errors is not as well-characterized, although norepinephrine and other neuromodulators and neuropeptides participate in fear learning. Here, we utilized fluorescent norepinephrine recordings over the course of fear learning in concert with reinforcement learning modeling to identify its role in the prediction of threat. By varying timing and sensory uncertainty in the formation of threat associations, we were able to define a precise computational role for norepinephrine in this process. Norepinephrine release approximates the strength of fear associations, and its temporal dynamics are compatible with a prediction error signal. Intriguingly, the release of norepinephrine is influenced by time and sensory feedback, serving as an antithesis of the classical reward prediction error role of dopamine. Thus, these results directly demonstrate a combined cognitive and affective role of norepinephrine in the prediction of threat, with implications for neuropsychiatric disorders such as anxiety and PTSD.

/pdf/prefrontal-norepinephrine-represents-a-threat-prediction-1n4d4fvn.pdf

Prefrontal norepinephrine represents a threat prediction error under uncertainty

The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats. 

Potentiation of cholinergic and corticofugal inputs to the lateral amygdala in threat learning.

Reappraising neutral stimuli as environmental threats reflects rapid and discriminative changes in sensory processing within the basolateral amygdala (BLA). To understand how BLA inputs are also reorganized during discriminative threat learning, we performed multi-regional measurements of acetylcholine (ACh) release, single unit spiking, and functional coupling in the mouse BLA and higher-order auditory cortex (HO-AC). During threat memory recall, sounds paired with shock (CS+) elicited relatively higher firing rates in BLA units and optogenetically targeted corticoamygdalar (CAmy) units, though not in neighboring HO-AC units. Functional coupling was potentiated for descending CAmy projections prior to and during CS+ threat memory recall but ascending amygdalocortical coupling was unchanged. During threat acquisition, sound-evoked ACh release was selectively enhanced for the CS+ in BLA but not HO-AC. These findings suggest that phasic cholinergic inputs facilitate discriminative plasticity in the BLA during threat acquisition that is subsequently reinforced through potentiated auditory corticofugal inputs during memory recall.

/pdf/potentiated-cholinergic-and-corticofugal-inputs-support-3bz8rwzz.pdf

Potentiated cholinergic and corticofugal inputs support reorganized sensory processing in the basolateral amygdala during auditory threat acquisition and retrieval

Summary Although the engagement of cholinergic signaling in threat memory is well established (Knox, 2016a), our finding that specific cholinergic neurons are requisite partners in a threat memory engram is likely to surprise many. Neurons of the basal forebrain nucleus basalis and substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA), whose activation are required for both the acquisition and retrieval of cued threat memory and innate threat response behavior. The retrieval of threat memory by the presentation of the conditioning tone alone elicits acetylcholine (ACh) release in the BLA and the BLA-projecting cholinergic neurons manifest immediate early gene responses and display increased intrinsic excitability for 2-5 hours following the cue-elicited memory response to the conditioned stimulus. Silencing cue-associated engram-enrolled cholinergic neurons prevents the expression of the defensive response and the subset of cholinergic neurons activated by cue is distinct from those engaged by innate threat. Taken together we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli via the BLA, demonstrating exquisite, functionally refined organization of specific types of memory within the cholinergic basal forebrain.

/pdf/basal-forebrain-cholinergic-neurons-are-part-of-the-threat-4ijwf524uf.pdf

Basal forebrain cholinergic neurons are part of the threat memory engram

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Basal forebrain cholinergic neurons are part of the threat memory engram