Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS-US association occur in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that transmit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that associative LTP in LA might be a mechanism for storing memories of the CS-US association. Here, we develop a detailed cellular hypothesis to explain how neural responses to the CS and US in LA could induce LTP-like changes that store memories during fear conditioning. Specifically, we propose that the CS evokes EPSPs at sensory input synapses onto LA pyramidal neurons, and that the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also causes the LA neuron to fire action potentials. The action potentials then back-propagate into the dendrites, where they collide with CS-evoked EPSPs, resulting in calcium entry through voltage-gated calcium channels (VGCCs). Although calcium entry through NMDARs is sufficient to induce synaptic changes that support short-term fear memory, calcium entry through both NMDARs and VGCCs is required to initiate the molecular processes that consolidate synaptic changes into a long-term memory.

Several regions in the rat brain contain neurons known as head-direction cells, which fire only when the rat's head is facing in a specific direction. Head-direction cells are influenced only by the direction of the head with respect to the static environmental surroundings, and not by the position of the head relative to the body. Each head-direction cell has its own preferred direction of firing, so that together, the population of cells provides a continuous signal of momentary directional heading. Here, head-direction cells were recorded from the post-subicular cortex (PSC) and anterodorsal nucleus (ADN) of the thalamus of freely moving rats. Cell activity was analyzed in relation to both momentary head direction, and the angular velocity of head turns. Head-direction cells in PSC maintained the same directional firing preference, regardless of the angular head velocity. By contrast, head-direction cells in ADN systematically shifted their directional firing preference, as a function of angular head velocity. The ADN cells always shifted their directional tuning peak to the left during clockwise head turns, and to the right during counterclockwise head turns. These results suggest that ADN neurons anticipate the future direction of the head, whereas PSC neurons encode the present direction of the head. Based on these findings, we hypothesize that neurons in PSC and ADN are reciprocally connected to form a thalamocortical circuit, which computes the directional position of the rat's head by integrating the angular motion of the head over time.

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We recorded neurons from the hippocampus of freely behaving rats during an auditory fear conditioning task. Rats received either paired or unpaired presentations of an auditory conditioned stimulus (CS) and an electric shock unconditioned stimulus (US). Hippocampal neurons (place and theta cells) acquired responses to the auditory CS in the paired but not in the unpaired group. After CS-US pairing, rhythmic firing of theta cells became synchronized to the onset of the CS. Conditioned responses of place cells were gated by their location-specific firing, so that after CS-US pairing, place cells responded to the CS only when the rat was within the cell's place field. These findings may help to elucidate how the hippocampus contributes to context-specific memory formation during associative learning.

A form of aversively motivated learning called fear conditioning occurs when a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US). US-evoked depolarization of amygdala neurons may instruct Hebbian plasticity that stores memories of the CS-US association, but the origin of US inputs to the amygdala is unknown. Theory and evidence suggest that instructive US inputs to the amygdala will be inhibited when the US is expected, but this has not been demonstrated during fear conditioning. Here we investigated neural pathways that relay US information to the amygdala by recording neurons in the amygdala and periaqueductal gray (PAG) during fear conditioning. US-evoked responses in both amygdala and PAG were inhibited by expectation. Pharmacological inactivation of the PAG attenuated US-evoked responses in the amygdala and impaired acquisition of fear conditioning, indicating that PAG may be an important part of the pathway that relays instructive signals to the amygdala.

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Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here we review recent electrophysiological, molecular, and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray (PAG) region, can be linked to prediction error and expectation modulation of fear learning as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signalling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit may represent a conserved mechanism for regulating fear learning in mammals.

Humans and animals can learn that specific sensory cues in the environment predict aversive events through a form of associative learning termed fear conditioning. This learning occurs when the sensory cues are paired with an aversive event occuring in close temporal proximity. Activation of lateral amygdala (LA) pyramidal neurons by aversive stimuli is thought to drive the formation of these associative fear memories; yet, there have been no direct tests of this hypothesis. Here we demonstrate that viral-targeted, tissuespecific expression of the light-activated channelrhodopsin (ChR2) in LA pyramidal cells permitted optical control of LA neuronal activity. Using this approach we then paired an auditory sensory cue with optical stimulation of LA pyramidal neurons instead of an aversive stimulus. Subsequently presentation of the tone alone produced behavioral fear responses. These results demonstrate in vivo optogenetic control of LA neurons and provide compelling support for the idea that fear learning is instructed by aversive stimulus-induced activation of LA pyramidal cells.ear conditioning is a simple form of associative learning that provides a powerful model system to study associative plasticity and memory formation (1-4). During fear conditioning, a neutral stimulus [termed the conditioned stimulus (CS)], often an auditory tone, is paired repeatedly with an aversive stimulus [termed the unconditioned stimulus (US)] and animals learn that the CS predicts the occurrence of the US. When the CS is encountered after learning, animals emit a stereotyped group of adaptive responses, including behavioral freezing and associated physiological adjustments, which together are termed the fear response.The lateral nucleus of the amygdala (LA) is a site of associative plasticity, where US-evoked depolarization of LA pyramidal neurons is thought to instruct plasticity at synapses formed by CS inputs onto the same neurons (5-7). Several lines of indirect evidence support the idea that this plasticity occurs as a result of a Hebbian mechanism through which depolarization of LA pyramidal neurons by the shock US coincident with weaker activation of the same cells by auditory CS inputs results in fear learning (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). This hypothesis makes the strong prediction that pairing an auditory CS with direct activation of LA pyramidal neurons as an US should be sufficient, in the absence of a shock US, to support fear learning and memory formation. Here we tested this hypothesis by substituting the aversive US with optical stimulation (19,20) of LA pyramidal neurons during learning, and we report that physiological activation of these cells results in fear conditioning. ResultsThe light activated channelrhodopsin (ChR2) (19,20) has been used in other neural systems to activate specific cell populations and produce learning (21-23). We took advantage of this technology and targeted ChR2 to pyramidal cells by in vivo viralmediated gene transfer. We used an adeno-associated virus (AAV) to express a...