The role of basal forebrain cholinergic neurons in fear and extinction memory

Abstract

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed.

Keywords: Contextual conditioning; Extinction recall; Fear conditioning; Fear extinction; Inhibitory avoidance; Magnocellular; Nucleus basalis.

Figure 1

Behavioral paradigms used to examine emotional memory (fear and extinction) in neuroscience experiments. Cartoons illustrate the paradigm and graphs adjacent to the cartoons illustrate the change in fear behavior during fear conditioning (FC), extinction training (ExTrain), and extinction testing (ExTest). A) Pavlovian fear conditioning. Freezing is used as the measure of fear in this paradigm. Often the conditioning and extinction contexts are different in this paradigm (represented by change in color), which can allow for separate measurement of cued and contextual fear and extinction memory. B) Conditioned fear suppression. In this paradigm, changes in operant performance are used as the measure of fear behavior, but a context shift is not typically used. C) Fear potentiated startle. This paradigm involves presentation of a white noise burst to elicit a startle reflex, which is typically measured by an accelerometer that transduces movement into an electrical signal. During conditioning and in the presence of the conditioned stimulus (CS) the startle reflex is enhanced. D) Inhibitory avoidance. This paradigm involves placing the animal in a light compartment that is connected to a dark compartment. Upon entering the dark compartment the animal then receives a footshock. Avoidance of the dark compartment after conditioning is the measure of fear behavior.

Figure 2

A) Schematic of the basal forebrain (BF) cholinergic neurons that project to fear and extinction circuits. BF neurons in the preoptic area are not being shown, because these neurons are rarely manipulated in studies that examine the effects of BF cholinergic manipulation on fear and extinction memory. NBM neurons are showed in dashed lines while MS/DBB neurons are showed in solid lines. B) Summarized schematic of the cholinergic synapse in fear and extinction circuits. Post and pre prefixes refer to whether receptors are pre or post synaptic. ChTrans – choline transporter,

Figure 3

Neurobiological processes via which BF amygdalopetal cholinergic neurons modulate emotional memory. A) Hypothetical circuit. Circles in red illustrate locus coeruleus neurons, green represent BF amygdalopetal cholinergic neurons, purple represent BLA principal neurons, and orange represent cortical input to BLA principal neurons. Components of the circuit that need verification are shown in dashed lines. B) Molecular processes by which BF amygdalopetal cholinergic neurons modulate emotional memory. Unknown mechanisms are shown as question marks or dashed lines. Decreased signaling is indicated by light blue arrows. C) Fear relevant electrophysiological processes by which BF amygdalopetal cholinergic neurons modulate BLA principal neurons. LC – locus coeruleus. m1AChR – muscarinic receptor type 1, nAChR – nicotinic receptor, IP3 – inositol triphosphate, IP3R – IP3 receptor, DAG – diacylglycerol, PIP2 – phosphatidylinositol biphosphate, PKC – protein kinase C.

Figure 4

Neurobiological processes via which NBM corticopetal cholinergic neurons modulate emotional memory. A) Neural circuits. NBM cholinergic neurons are in green, LC neurons are in red, central amygdala (CeA) neurons are in yellow, and NBM GABAergic neurons are in purple. Components of the neural circuit that need verification are shown in dashed lines. B) Electrophysiological mechanisms. NBM corticoptal cholinergic input to the PFC increases the slow-wave components (1-4Hz) of the PFC local field potential (LFP) and may disrupt decreases in slow wave PFC LFP during fear conditioning. These effects may mediate the disruptive effect NBM corticopetal cholinergic lesions have on fear memory in the conditioned suppression paradigm. preFC – pre fear conditioning.

Figure 5

Neurobiological processes via which MS/DBB cholinergic neurons modulate emotional memory. A) Hypothetical circuit. Components of the circuit that need verification are shown in dashed lines. B) Molecular processes by which MS/DBB cholinergic neurons modulate emotional memory. Unknown mechanisms are shown as question marks or dashed lines. Decreased signaling is indicated by light blue arrows.