Michael S. Fanselow

Are The Dorsal and Ventral Hippocampus functionally distinct structures

One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus).

The neuroanatomical and neurochemical basis of conditioned fear

After a few pairings of a threatening stimulus with a formerly neutral cue, animals and humans will experience a state of conditioned fear when only the cue is present. Conditioned fear provides a critical survival-related function in the face of threat by activating a range of protective behaviors. The present review summarizes and compares the results of different laboratories investigating the neuroanatomical and neurochemical basis of conditioned fear, focusing primarily on the behavioral models of freezing and fear-potentiated startle in rats. On the basis of these studies, we describe the pathways mediating and modulating fear. We identify several key unanswered questions and discuss possible implications for the understanding of human anxiety disorders.

Conditional and unconditional components of post-shock freezing

Rats received shocks in one apparatus, and post-shock “freezing” was then assessed in that apparatus or in a different one. The assessment of freezing was made immediately after shock or after a 24-hour delay. Post-shock freezing was reduced when the animals were tested in a different apparatus from that in which shocks had been administered. No reduction in freezing was caused by the 24-hour delay. All the post-shock freezing was therefore attributable to contextual cues and to generalization between contexts. This pattern of results suggests that post-shock freezing is entirely produced by conditioned fear elicited by cues associated with shock and that no part of post-shock freezing is an unconditional response (UR) directly elicited by shock.

Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala

The encoding view provides a parsimonious account of the multiple convergent lines of evidence for the ABL’s role in fear conditioning. We do not dispute the notion that activation of the ABL can facilitate consolidation of information in other structures, such as the hippocampus, other cortical areas, or the striatum (4xMechanisms of emotional arousal and lasting declarative memory. Cahill, L and McGaugh, J.L. Trends Neurosci. 1998; 21: 294–299Abstract | Full Text | Full Text PDF | PubMed | Scopus (952)See all References, 27xAmygdala modulation of multiple memory systems (hippocampus and caudate-putamen) . Packard, M.G and Teather, L.A. Neurobiol. Learn. Mem. 1998; 69: 163–203Crossref | PubMed | Scopus (214)See all References). Rather, we argue that the ABL is involved in the encoding of fear memory and the modulation of memory functions of other structures.While we believe that the ABL is essential to the implicit learning that constitutes fear conditioning, we are not proposing that all of the plasticity relevant to fear conditioning necessarily occurs within the ABL. It seems possible that the ABL, while essential, is also part of a distributed network that encodes the fear memory. For example, as noted, there is compelling evidence that plastic changes occur in regions that are afferent to the ABL, such as thalamic and cortical sensory systems that process CSs (see Weinberger 1995xRetuning the brain by fear conditioning. Weinberger, N.M. See all ReferencesWeinberger 1995). Additionally, cortical areas that are both afferent and efferent to the ABL (e.g., perirhinal cortex, the hippocampal formation, and sensory cortex) may participate with the ABL in the long-term encoding of fear. It remains for future research to determine whether these distributed representations exist and, if so, to unravel their nature.‡To whom correspondence should be addressed (e-mail: fanselow@ucla.edu).

Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats

Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl-D-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

Neural organization of the defensive behavior system responsible for fear

This paper applies the behavior systems approach to fear and defensive behavior, examining the neural circuitry controlling fear and defensive behavior from this vantage point. The defensive behavior system is viewed as having three modes that are activated by different levels of fear. Low levels of fear promote pre-encounter defenses, such as meal-pattern reorganization. Moderate levels of fear activate post-encounter defenses. For the rat, freezing is the dominant post-encounter defensive response. Since this mode of defense is activated by learned fear, forebrain structures such as the amygdala play a critical role in its organization. Projections from the amygdala to the ventral periaqueductal gray activate freezing. Extremely high levels of fear, such as those provoked by physical contact, elicit the vigorous active defenses that compose the circa-strike mode. Midbrain structures such as the dorsolateral periaqueductal gray and the superior colliculus play a crucial role in organizing this mode of defense. Inhibitory interactions between the structures mediating circa-strike and post-encounter defense allow for the rapid switching between defensive modes as the threatening situation varies.

A perceptual–defensive–recuperative model of fear and pain.

A model of fear and pain is presented in which the two are assumed to activate totally different classes of behavior. Fear, produced by stimuli that are associated with painful events, results in defensive behavior and the inhibition of pain and pain-related behaviors. On the other hand, pain, produced by injurious stimulation, motivates recuperative behaviors that promote healing. In this model injurious stimulation, on the one hand, and the expectation of injurious stimulation, on the other hand, activate entirely different motivational systems which serve entirely different functions. The fear motivation system activates defensive behavior, such as freezing and flight from a frightening situation, and its function is to defend the animal against natural dangers, such as predation. A further effect of fear motivation is to organize the perception of environmental events so as to facilitate the perception of danger and safety. The pain motivation system activates recuperative behaviors, including resting and body-care responses, and its function is to promote the animals recovery from injury. Pain motivation also selectively facilitates the perception of nociceptive stimulation. Since the two kinds of motivation serve different and competitive functions, it might be expected that they would interact through some kind of mutual inhibition. Recent research is described which indicates that this is the case. The most important connection is the inhibition of pain by fear; fear has the top priority. This inhibition appears to be mediated by an endogenous analgesic mechanism involving the endorphins. The model assumes that fear triggers the endorphin mechanism, thereby inhibiting pain motivation and recuperative behaviors that might compete with effective defensive behavior.

Contextual fear, gestalt memories, and the hippocampus

This review examines the relationship between exploration and contextual fear conditioning. The fear acquired to places or contexts associated with aversive events is a form of Pavlovian conditioning. However, an initial period of exploration is necessary to allow the animal to form an integrated memory of the features of the context before conditioning can take place. The hippocampal formation plays a critical role in this process. Cells within the dorsal hippocampus are involved in the formation, storage and consolidation of this integrated representation of context. Projections from the subiculum to the nucleus accumbens regulate the exploration necessary for the acquisition of information about the features of the context. This model explains why electrolytic but not excitotoxic lesions of the dorsal hippocampus cause enhanced exploratory activity but both cause deficits in contextual fear. It also explains why retrograde amnesia of contextual fear is greater than anterograde amnesia.

NF-kappa B functions in synaptic signaling and behavior.

Ca2+-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-κB transcription factor by a pathway requiring the Ca2+/calmodulin-dependent kinase CaMKII and local submembranous Ca2+ elevation. The p65:p50 NF-κB form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-κB. Activated NF-κB moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-κB nuclear translocation and gene activation.

Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear

The effects of amygdala, hippocampus, and periaqueductal gray (PAG) lesions on contextual fear conditioning in rats were examined. Freezing behavior served as the measure of conditioning. Unlesioned control animals showed reliable conditional freezing in the testing chamber when observed both immediately and 24 hr after footshocks. In contrast, rats with amygdala or ventral PAG lesions exhibited a significant attenuation in freezing both immediately and 24 hr after the shocks. Dorsal PAG lesions had no effect on freezing at either time. Animals with hippocampal lesions displayed robust freezing behavior immediately following the shock, even though they showed a marked deficit in freezing 24 hr after the shock. These results indicate that there are anatomically dissociable short- and long-term conditional fear states.