Passive (Inhibitory) Avoidance, Fear Learning

views updated


Fear learning is the process of gathering information about the internal and external environment in situations that evoke fear. Fear learning is the first step toward creating memories for fearful events (fear memories), which are robust and represent a long-lasting record of the acquired information that is capable of modifying behavior when retrieved. Like other forms of learning, fear learning (fear memory acquisition) is followed first by memory consolidation, a period of time when memories are still labile and can be modulated (enhanced or impaired), and then by memory storage (McGaugh, 2000).

Because memories cannot be directly observed and assayed, their existence is, by necessity, inferred from changes in behavior following an experience (Cahill, McGaugh, and Weinberger, 2001). Thus, to study learning and memory, subjects are interrogated by observing their performance in carefully designed behavioral tasks. In the study of fear learning and memory, the most widely used tasks are passive (inhibitory) avoidance and fear conditioning. This entry will focus on the former task and will discuss how its use has advanced the understanding of brain structures and neuromodulatory systems involved in consolidating and storing memories for fearful events. Although this presentation is based on findings obtained in rats and mice, passive avoidance has also been instrumental in understanding memory processes in chicks (Rose, 2000) and humans (Cahill and McGaugh, 1998).

Passive (Inhibitory) Avoidance

Memory in a passive avoidance task is inferred from the delay of a response that was readily made before the training. Because delaying a response is an active process, some investigators refer to the task as inhibitory, rather than passive, avoidance (Cahill and McGaugh, 1998; Izquierdo, Medina, and Barros, 1999). Passive (inhibitory) avoidance, or PA/IA, experiments are conducted in a two-compartment behavioral apparatus, where one compartment is designed to be naturally preferred by the animal (see Figure 1). During training, the animal is placed in the less-preferred compartment and the latency to enter the preferred compartment is noted. Upon completely entering the preferred compartment, the animal receives one or more inescapable foot shocks of a specified intensity and duration. The information the animal gathers during the training is fear learning. At a retention test, conducted hours, days, or months later, the animal is returned to the previously less-preferred compartment and the latency to enter the shock compartment, which at this point is not electrified, is measured. This measure (retention latency) is used to infer the animal's memory for the fearful experience—the longer the retention latency, the better the memory. A long retention latency indicates a significant modification in the animal's behavior, as it contrasts with the animal's low initial entrance latency displayed before the training.

PA/IA testing has several features that make it a valuable tool for investigating brain systems involved in memory acquisition, consolidation, and retrieval. It is simple to administer and thus easy to replicate across laboratories, yet it is complex enough to engage multiple brain regions and neurotransmitter systems (Ambrogi Lorenzini et al., 1999; Izquierdo, Medina, and Barros, 1999; McGaugh, Ferry, Vazdarjanova, and Roozendaal, 2000). In addition, PA/IA is ethologically relevant in that it promotes fast learning, usually after one trial (in nature, an animal may not survive to pass on its genes if it does not learn to recognize and avoid a predator after a single encounter). One-trial learning provides a clear time stamp of when learning occurred. In combination with post-training manipulations, which selectively affect memory consolidation but not acquisition or retrieval (McGaugh, 1989), PA/IA training provides researchers the ability to study the brain mechanisms involved in consolidation of explicit-declarative memory for fearful events.

What Kind of Memory Does the Retention Latency Measure Represent?

Arguably, retention latency measured in PA/IA may reflect only a procedural memory (i.e., entering a place is aversive) (Wilensky, Schafe, and LeDoux, 2000). However, during PA/IA animals could acquire both explicit-declarative memories, such as those acquired during Pavlovian contextual fear conditioning ("I got shocked in this place"), and implicit-procedural memories that reflect a response-reinforcement contingency. Because acquiring procedural memories takes many more trials than acquiring explicit-declarative memories (Packard and McGaugh, 1996), measuring retention latencies after one-trial PA/IA most likely reflects explicit-declarative fear memories. Moreover, when the two types of memory were experimentally pitted against each other in a modified avoidance task, animals unambiguously expressed explicit-declarative fear memories. In this test, rats were trained on an active avoidance task by being repeatedly placed in the preferred compartment, each time shocked until they entered the less-preferred (light) compartment, and then tested by being placed in the light compartment. By showing high retention latencies, the rats indicated that they had learned where they had received foot shocks (explicit memory), rather than that they had to perform a response (procedural memory) (Parent, West, and McGaugh, 1994). Additionally, latencies to enter a compartment where foot shock was experienced can be successfully used to assess memory for contextual fear conditioning, a task in which receiving foot shocks is not contingent on any one particular response (Vazdarjanova and McGaugh, 1998).

Factors Involved in Consolidation of Memory for PA/IA

Stress hormones (adrenaline [or epinephrine] and glucocorticoids), when injected after training at the time when they are normally released by the adrenal glands following an emotional experience, can modulate the memory strength for one-trial PA/IA training. This modulation is dose-dependent (low to medium levels of stress hormones are memory enhancing, whereas high levels are memory impairing) and time-dependent (the effects are most pronounced when the treatments are administered immediately after training). Consistent with the idea that these hormones are endogenously released as a result of an emotional experience, memory is impaired by removing the adrenals, blocking peripheral β-adrenoceptors, or blocking the synthesis of glucocorticoids. Although their effects on memory consolidation are similar, adrenaline and glucocorticoids exert their effects via different pathways. Glucocorticoids are lipophilic and readily cross the blood-brain barrier, thus directly affecting memory consolidation in several brain regions by activating glucocorticoid receptors. When glucocorticoid receptor agonists are administered directly into the basolateral amygdala, hippocampus, or nucleus of the solitary tract (NTS), they enhance memory for PA/IA. The effects of glucocorticoids on memory appear to be mediated by the basolateral amygdala, as lesions of this region or inactivation of the amygdala's β-adrenoceptors block the memory-modulatory effects of peripheral and intrahippocampal or intra-NTS glucocorticoid treatments (Roozendaal, 2000).

Unlike glucocorticoids, adrenaline does not readily pass the blood-brain barrier and its effects on memory consolidation are mediated by β-adrenoceptors on the vagus nerve. Activation of the vagus nerve stimulates noradrenergic neurons in the NTS directly and noradrenergic neurons in the locus coeruleus indirectly. Thus, peripherally released adrenaline leads to centrally released noradrenaline. Although noradrenaline can modulate memory consolidation for PA/IA by acting directly on neurons in the basolateral amygdala, hippocampus, and entorhinal cortex (Izquierdo, Medina, and Barros, 1999), noradrenergic activation of the basolateral amygdala is of primary importance. Stress induces the release of noradrenaline in this region, and activation of the amygdala's β-adrenoceptors reverses the memory-impairing effects of GABAergic (gammaaminobutyric acid) and opioid agonists, while blocking of the β-adrenoceptors blocks the memory enhancement produced by GABAergic and opioid antagonists. The effectiveness of the basolateral amygdala's β-adrenoceptors themselves depends on the activation of glucocorticoid receptors in this region (see Figure 2; also McGaugh, Ferry, Vazdarjanova, and Roozendaal, 2000).

Adrenergic, glucocorticoid, and cholinergic memory modulatory treatments produced by either systemic treatments or direct manipulations of the amygdala are reversed by lesions of the stria terminalis, one of the two major input-output pathway of the amygdala. Thus, the amygdala appears to modulate memory storage in target areas of the stria terminalis (McGaugh, Ferry, Vazdarjanova, and Roozendaal, 2000).

Memory for PA/IA is also modulated by glucose (the release of which is enhanced by adrenaline), vasopressin, and substance P, as well as cholinergic, GABA-ergic, dopaminergic, serotonergic, and opioid agents (Gold, 1995; Koob et al., 1991; McGaugh, 1989; Izquierdo, Medina, and Barros, 1999; Zhang, Berbos, and Wiley, 1996; Riekkinen, Kuitunen, and Riekkinen, 1995).

All neuromodulatory treatments discussed thus far appear to affect memory storage not only for PA/IA but for emotional experiences in general, as similar findings have been shown in other emotionally motivated tasks. Predictions based on the reported findings in rats and mice have been supported by results obtained in human subjects (Cahill and McGaugh, 1998).

Researchers debate whether the described mechanisms of memory consolidation for PA/IA, notably the role of the basolateral amygdala in memory storage, are the same as those for fear conditioning (Fanselow and LeDoux, 1999; Cahill, Weinberger, Roozendaal, and McGaugh, 1999; Maren, 1999; Vazdarjanova, 2000). Although the basolateral amygdala plays a modulatory role in memory consolidaton of PA/IA, it is probably also the site of memory storage for fear conditioning. This conclusion is based mainly on the observation that pretraining or pretest lesions or inactivation (both general and NMDA-receptor specific) of this brain region lead to decreased freezing behavior, a typical measure used to assess memory for fear conditioning. In addition, the basolateral amygdala develops LTP-like (long-term potentiation) plasticity as a result of auditory fear conditioning. However, both lines of evidence are also consistent with a modulatory role of the basolateral amygdala in fear conditioning. Thus, if disruption of activity in this region leads to decreased strength of memories for fear conditioning, animals will be less likely to display freezing, a behavior that indicates high levels of fear, while other measures of memory may be still evident. Consistent with this hypothesis are findings that following contextual fear conditioning, rats with complete lesions of the basolateral amygdala do not show freezing, but do display training-induced avoidance of the place where they had received foot shocks (Vazdarjanova and McGaugh, 1998). Furthermore, physiological plasticity following fear conditioning is not unique to the basolateral amygdala but is present in multiple brain regions (Mcintosh and Gonzalez-Lima, 1998; Poremba and Gabriel, 2001), suggesting that fear memories are likely encoded and stored in a distributed neural network across several brain regions.

Temporal Pattern of Memory Consolidation for PA/IA

Studies of functional inactivation of selective brain regions by anesthetics that block sodium channels, or by increasing inhibition through GABA-A receptors, have shown that memory consolidation for PA/IA occurs over a long period of time and involves sequentially a multitude of brain regions. Functional integrity of the hippocampus, medial septum, baso-lateral amygdala, nucleus of the solitary tract, and several cortical regions (insular, anterior prefrontal [Fr2], and posterior cingulated) is required during an early phase of memory consolidation (immediately and up to 1.5 hours after training), whereas that of the entorhinal and parietal cortecies is required during a later phase (0.5 to 3 hours or 1 to 3 hours, respectively). Finally, the functional integrity of brain regions that release neuromodulators in the hippocampus, amygdala, and cortex—such as the nucleus basalis, substantia nigra, and parabrachial nucleus—is required for a couple of days after training. The duration of memory consolidation appears to depend on the intensity of the training—the higher the foot-shock stimulus, the quicker the consolidation (Ambrogi Lorenzini et al., 1999; Bermúdez-Rattoni, Introini-Collison, and McGaugh, 1991; Izquierdo, Quillfeldt, and Medina, 1997; Mello e Souza, Vianna, and Izquierdo, 2000).

Conceptual Advances Facilitated by the Use of One-Trial PA/IA

The use of PA/IA and timed manipulations after training has helped identify the neuromodulatory systems and their interactions in brain regions, notably the basolateral amygdala, that modulate the consolidation of explicit memories for fearful events. PA/IA studies also revealed that memory consolidation is a dynamic process that occurs over hours to days and depends sequentially on networks of neurons distributed among several brain regions. The shift over time in the dependence of memory consolidation to cortical regions also indicates that, consistent with early predictions (Gerard, 1961), the cortex appears to be the ultimate repository for explicit-declarative long-term emotional memories. Finally, because PA/IA is useful in assessing both short-term memory (developing within seconds and lasting minutes to hours) and long-term memory (developing over time and lasting hours to years) (McGaugh, 2000) in the same subjects, it enabled the first demonstration in mammals that the processes underlying these two types of memory are independent. Fifteen different pharmacological manipulations that affect specific receptors or molecular cascades in the hippocampus, entorhinal, and parietal cortex impair short-term memory without affecting long-term memory (Izquierdo, Medina, and Barros, 1999). Thus, the development of long-term memory does not require intact short-term memory. The conceptual advances afforded by the use of PA/IA underscore the importance of this paradigm as a model system for studying emotional learning and memory processes.



Ambrogi Lorenzini, C., Baldi, E., Bucherelli, C., Sacchetti, B., and Tassoni, G. (1999). Neural topography and chronology of memory consolidation: A review of functional inactivation findings. Neurobiology of Learning and Memory 71 (1), 1-18.

Bermúdez-Rattoni, F., Introini-Collison, I. B., and McGaugh, J. L. (1991). Reversible inactivation of the insular cortex by tetrodotoxin produces retrograde and anterograde amnesia for inhibitory avoidance and spatial learning. Proceedings of the National Academy of Sciences of the United States of America 88, 5,379-5,382.

Cahill, L., and McGaugh, J. L. (1998). Mechanisms of emotional arousal and lasting declarative memory. Trends in Neuroscience 21 (7), 294-299.

Cahill, L., McGaugh, J. L., Weinberger, N. M. (2001). The neurobiology of learning and memory: Some reminders to remember. Trends in Neurosciences 24 (10), 578-581.

Cahill, L., Weinberger, N. M., Roozendaal, B., and McGaugh, J. L. (1999). Is the amygdala a locus of "conditioned fear"? Some questions and caveats. Neuron 23, 227-228.

Fanselow, M., and LeDoux, J. (1999). Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23, 229-232.

Gerard, R. W. (1961). The fixation of experience. In A. Fessard, R. W. Gerard, and J. Konorski, eds., Brain mechanisms and learning: A symposium. Springfield, IL: Thomas.

Gold, P. E. (1995). Modulation of emotional and non-emotional memories: Same pharmacological systems, different neuroanatomical systems. In J. L. McGaugh, N. M. Weinberger, and G. Lynch, eds., Brain and memory: Modulation and mediation of neuroplasticity. New York: Oxford University Press.

Izquierdo, I., Medina, J. H., and Barros, D. M. (1999). Separate mechanisms for short-and long-term memory. Behavioural Brain Research 103 (1), 1-11.

Izquierdo, I., Quillfeldt, J. A., and Medina, J. H. (1997). Sequential role of hippocampus and amygdala, entorhinal cortex and parietal cortex in formation and retrieval of memory for inhibitory avoidance in rats. European Journal of Neuroscience 9 (4), 786-793.

Koob, G. F. et al. (1991). Vasopressin and learning: Peripheral and central mechanisms. In R. Frederickson, J. L. McGaugh, and D. L. Felten, eds., Peripheral signaling of the brain: Role in neural-immune interactions, learning and memory. Toronto: Hogrefe and Huber.

Maren, S. (1999). Long-term potentiation in the amygdala: A mechanism for emotional learning and memory. Trends in Neurosciences 22 (12), 561-567.

McGaugh, J. L. (1989). Dissociating learning and performance: Drug and hormone enhancement of memory storage. Brain Research Bulletin 23, 339-345.

—— (2000). Neuroscience: Memory—a century of consolidation. Science 287 (5,451), 248-251.

McGaugh, J. L., Ferry, B., Vazdarjanova, A., and Roozendaal, B. (2000). Amygdala: Role in modulation of memory storage. In John P. Aggleton, ed., The Amygdala: A functional analysis, 2nd edition. London: Oxford University Press.

Mcintosh, A., and Gonzalez-Lima, F. (1998). Large-scale functional connectivity in associative learning: Interactions of the rat auditory, visual, and limbic systems. Journal of Neurophysiology 80, 3,148-3,162.

Mello e Souza, T., Vianna, M. R. M., and Izquierdo, I. (2000). Involvement of the medial precentral prefrontal cortex in memory consolidation for inhibitory avoidance learning in rats. Pharmacology, Biochemistry, and Behavior 66 (3), 615-622.

Packard, M. G., and McGaugh, J. L. (1996). Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiology of Learning and Memory 65, 65-72.

Parent, M. B., West, M., and McGaugh, J. L. (1994). Memory of rats with amygdala lesions induced thirty days after footshock-motivated escape training reflects degree of original training. Behavioral Neuroscience 108 (6), 1,080-1,087.

Poremba, A., and Gabriel, M. (2001). Amygdala efferents initiate auditory thalamic discriminative training-induced neuronal activity. Journal of Neuroscience 21 (1), 270-278.

Riekkinen Jr., P., Kuitunen, J., and Riekkinen, M. (1995). Effects of scopolamine infusions into the anterior and posterior cingulate on passive avoidance and water maze navigation. Brain Research 685 (1-2), 46-54.

Roozendaal, B. (2000). Glucocorticoids and the regulation of memory consolidation. Psychoneuroendocrinology 25 (3), 213-238.

Rose, S. P. (2000). God's organism? The chick as a model system for memory studies. Learning and Memory 7 (1), 1-17.

Vazdarjanova, A. (2000). Does the basolateral amygdala store memories for emotional events? Trends in Neurosciences 23 (8), 345.

Vazdarjanova, A., and McGaugh, J. L. (1998). Basolateral amygdala is not critical for cognitive memory of contextual fear conditioning. Proceedings of the National Academy of Sciences of the United States of America 95, 15,003-15,007.

Wilensky, A. E., Schafe, G. E., and LeDoux, J. E. (2000). The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. Journal of Neuroscience 20 (18), 7,059-7,066.

Zhang, Z. J., Berbos, T. G., and Wiley, R. G. (1996). Loss of nucleus basalis magnocellularis, but not septal, cholinergic neurons correlates with passive avoidance impairment in rats treated with 192-saporin. Neuroscience Letters 203 (3), 214-218.