Animal Fear Conditioning

Animal research has also been demonstrating the interplay between the hippocampus and amygdala in fear conditioning. The amygdala facilitates the acquisition of the conditioned fear response to both the conditioned stimulus (CS) and foreground context. A context is an interrelated assortment of sensory environmental cues that coexist with any given CS. The hippocampus facilitates fear conditioning learning to (peripheral) background context. Lesioning either of these structures produces reductions in freezing behaviors (Phillips & LeDoux, 1992, 1994).

Hippocampal lesion induced temporally graded retrograde amnesia also occurs during fear conditioning. Post-training lesions of the hippocampus (lesions occurring after fear conditioning training) at one day produce an early time limited learning impairment in recognizing fear-producing contexts or environments (Anagnostaras, Maren, & Fanselow, 1999). Post-training tetrodotoxin (TTX) inactivation of the hippocampus at 1.5 hours, basolateral amygdala at two days, and perirhinal cortex at 8 days disrupted fear conditioning learning and consolidation in a temporally induced manner (Sacchetti, Lorenzini, Baldi, Tassoni, & Bucherelli, 1999). Hippocampal lesions 7- 28 days after training have no effect (Kim & Fanselow, 1992). Rats receiving pretraining neurotoxic hippocampal lesions are able to acquire contextual fear conditioning freezing during the training session, one and 28 days later (Maren, Aharonov, & Fanselow, 1997). These findings correlate with those in the human with MTL damage having spared conditioning abilities (Weiskrantz & Warrington, 1979). Interestingly the same animal lesioning studies and those with amygdaloid lesions (Peinado-Manzano, 1988) document significantly increased motor activity. These findings may also be suggestive of increased striatal response learning and expression as noted earlier.

The amygdala receives auditory input and relay from the auditory thalamus and sensory cortex. It transmits fear-related information to corticohippocampal regions and arousal-related input to subcortical structures (LeDoux, 1998). With discrete lesioning of its lateral nucleus, behavioral freezing deficits have been noted to fear producing contexts and to the unpaired CS due to disruptions in the US-CS association (Goosen & Maren, 2001; Nader, Majidishad, Amorapanth, & LeDoux, 2001). The lateral nucleus normally undergoes neural changes that help the CS to take on the aversive qualities of the US during short and later term memory (Blair, Schafe, Bauer, Rodriguez, & LeDoux, 2001). According to the animal research, both the amygdala and hippocampus make important contributions to the gestalt of fear conditioning experience, i.e. the amygdala to object, source and context and the hippocampus to context alone.

The amygdala’s lateral nucleus of the amygdala also relays neural information through its projections with its central nucleus (LeDoux, 2000). The central nucleus’s projections to the brainstem modulate reactive reflexive fear responses and those for autonomic arousal and increased cardiovascular output (Carrive, 2000; Gallagher & Holland, 1994). Its lesioning impairs the acquisition of freezing behaviors (Nader et al., 2001) due to discontinuities with autonomic centers for arousal.

The formation of fear conditioning’s US-CS association also produces a 33% decrease and suppression in the number of proliferating cells (also known as neurogenesis) in the dentate gyrus of the hippocampus proper with no change in cell number (Pham, McEwen, LeDoux, & Nader, 2005). The dentate gyrus has been associated with acquisition-related orthogonal input that is needed for the development of a rapidly developing and meaningful contextual representation to support and aid retrievability (Lee & Kesner, 2004). In fact, the amygdala normally blocks hippocampal consolidation-related cellular long-term potentiation (LTP) during overwhelming, uncontrollable, and chronic stress like during rat’s tail shock and fear conditioning. Electrolytic lesions of the amygdala block this ability and allow for more normalized hippocampal LTP. Chronic stress on the other hand enhances fear conditioning learning and performance of stimulus-response strategies (Kim & Diamond, 2002; Kim, Lee, Han, & Packard, 2001). The animal research illustrates that the amygdala has a modulatory effect on the hippocampus during fear conditioning and stress.

References

Anagnostaras, S.G., Maren, S., & Fanselow, M.S. (1999). Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. Journal of Neuroscience, 19(3), 1106-14.

Blair, H.T., Schafe, G.E., Bauer, E.P., Rodriguez, S.M., & LeDoux, J.E. (2001). Synaptic plasticity in the lateral amygdala: A cellular hypothesis of fear conditioning. Learning and Memory, 8(5), 229-242.

Carrive, P. (2000). Conditioned fear to environmental context: cardiovascular and behavioral components in the rat. Brain Research, 858(2), 440-445.

Gallagher, M., & Holland, P.C. (1994). The amygdala complex: multiple roles in associative learning and attention. Proceedings National Academy of Sciences U.S.A., 91(25), 11771-11776.

Goosens, K.A., & Maren, S. (2001). Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learning and Memory, 8(3), 148-155.

Kim, J.J., & Diamond, D.M. (2002). The stressed hippocampus, synaptic plasticity and lost memories. Nature Reviews in Neuroscience, 3(6), 453-462.

Kim, J.J., & Fanselow, M.S. (1992). Modality-specific retrograde amnesia of fear. Science, 256(5057), 675-677.

Kim, J.J., Lee, H.J., Han, J.S., & Packard, M.G. (2001). Amygdala is critical for stress-induced modulation of hippocampal long-term potentiation and learning. Journal of Neuroscience, 21(14), 5222-5228.

LeDoux, J. (1998). Fear and the brain: where have we been, and where are we going? Biological Psychiatry, 44(12), 1229-1238.

LeDoux, J.E. (2000). Emotion circuits in the brain. Annual Review in Neuroscience, 23, 155-184.

Lee, I., & Kesner, R.P. (2004). Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning. Hippocampus, 14(3), 301-310.

Maren, S., Aharonov, G., & Fanselow, M.S. (1997). Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behavioral Brain Research, 88, 261-274.

Nader, K., Majidishad, P., Amorapanth, P., & LeDoux, J.E. (2001). Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learning and Memory, 8(3), 156-163.

Peinado-Manzano, A. (1988). Effects of bilateral lesions of the central and lateral amygdala on free operant successive discrimination. Behavioural Brain Research, 29(1-2), 61-71.

Pham, K., McEwen, B.S., LeDoux, J.E., & Nader, K. (2005). Fear learning transiently impairs hippocampal cell proliferation. Neuroscience, 130(1), 17-24.

Phillips, R.G., & LeDoux, J.E. (1992). Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience, 106(2), 274-285.

Phillips, R.G., & LeDoux, J.E. (1994). Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learning and Memory, 1(1), 34-44.

Sacchetti, B., Lorenzini, C.A., Baldi, E., Tassoni, G., & Bucherelli, C. (1999). Auditory thalamus, dorsal hippocampus, basolateral amygdala, perirhinal cortex roles in the consolidation of conditioned freezing to context and to acoustic conditioned stimulus in the rat. Journal of Neuroscience, 19(21), 9570-9578.

Weiskrantz, L., & Warrington, E.K. (1979). Conditioning in amnesic patients. Neuropsychologia, 17, 187-194.

Extinction-Animal Research

Fear-related extinction evolves when a fear producing CS or context is presented in absence of a US to cause its learned unpairing. Extinction learning reflects a CS-no US fear association (or CR-no fear) association superimposed on a fear producing CS-fear (or CR-fear) association (Garcia, 2002; Vianna et al., 2004). Extinction does not evolve from disuse and is not equivalent to forgetting. Therefore, the mere passage of time is not sufficient for extinction to occur, but reexposure to the actual CS without the aversive stimulus is required until the CR disappears.

Extinction is reflective of cortical inhibition of stress arousal (Pitman, Shalev, & Orr, 2000). It is mediated by discrete brain regions like the medial prefrontal cortex (mPFC). With the start of extinction training (i.e. unpairing CS) this region’s neurons incrementally increase neural activity. Neural activity in this region has been positively correlated with reduced fear reactivity and negatively correlated with fear induced freezing behaviors (Milad & Quirk, 2002). According to neurophysiological recordings in the rodent, this region’s neurons are very sensitive to the presence of aversive stimuli. MPFC neurons reactively reduce and depress spontaneous activity to conditioned fear stimuli in response to fear induced abnormal amygdala modulation (Garcia, Vouimba, Baudry, & Thompson, 1999; Herry & Mons, 2004). Medial PFC lesions prior to fear conditioning impair the later development of extinction (Morgan, Romanski, & LeDoux, 1993). Interestingly post-training lesions have marginal effects on extinction training but significantly impair extinction training performance after the later spontaneous recovery of fear conditioning (Morgan, Schulkin, & LeDoux, 2003). These findings suggest that an intact mPFC is needed at the time of fear conditioning’s acquisition to allow for the later expression of extinction. These findings also suggest a role for the mPFC in the early acquisition phase of fear conditioning learning; its activity and influence persist throughout the extinction phase.

References

Garcia, R. (2002). Post-extinction of conditioned fear: between two CS-related memories. Learning and Memory, 9(6) 361-3.

Garcia, R., Vouimba, R.M., Baudry, M., & Thompson, R.F. (1999). The amygdala modulates prefrontal cortex activity relative to conditioned fear. Nature, 402(6759), 294-296.

Herry, C., & Mons, N. (2004). Resistance to extinction is associated with impaired immediate early gene induction in medial prefrontal cortex and amygdala. European Journal of Neuroscience, 20(3), 781-790.

Milad, M.R., & Quirk, G.J. (2002). Neurons in medial prefrontal cortex signal memory for fear extinction. Nature, 420(6911), 70-74.

Morgan, M.A., Romanski, L.M., & LeDoux, J.E. (1993). Extinction of emotional learning. Contribution of medial prefrontal cortex. Neuroscience Letters, 163, 109-113.

Morgan, M.A., Schulkin, J., & LeDoux, J.E. (2003). Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training. Behavioral Brain Research, 146(1-2), 121-130.

Pitman, R.K., Shalev, A.Y., & Orr, S.P. (2000). Post-traumatic stress disorder: emotion, conditioning, and memory. In: M.S. Gazzaniga (Ed.), The cognitive neurosciences, 2nd ed. (pp. 1133-1148). Cambridge, MA: MIT Press.

Vianna, M.R., Coitinho, A., & Izquierdo, I. (2004). Role of the hippocampus and amygdala in the extinction of fear-motivated learning. Current Neurovascular Research, 1, 55-60.