The smell of danger: a behavioral and neural analysis of predator odor-induced fear

The odors of predators used in animal models provide, in addition to electric footshock, an important means to investigate the neurobiology of fear. Studies indicate that cat odor and trimethylthiazoline (TMT), a synthetic compound isolated from fox feces, are often presented to rodents to induce fear-related responses including freezing, avoidance, stress hormone and, in some tests, risk assessment behavior. Furthermore, we report that different amounts of cat odor impregnated on small-, medium-, or large-sized cloths impact the display of fear-related behavior when presented to rats. That is, rats exposed to a large cat odor containing cloth exhibit an increase in fear behavior, particularly freezing, which remains at high levels in habituation tests administered over a period of 7 days. The large cloth also induces a long-lasting increase in avoidance behavior during repeated habituation and extinction tests. A review of the brain regions involved in predator odor-induced fear behavior indicates a modulatory role of the medial amygdala, bed nucleus of the stria terminalis, and dorsal premammillary nucleus. In addition, the basolateral amygdala is involved in fear behavior induced by cat odor but not TMT, and the central amygdala does not appear to play a major behavioral role in predator odor-induced fear. Future research involving the use of predator odor is likely to rapidly expand knowledge on the neurobiology of fear, which has implications for understanding fear-related psychopathology.     

Strain differences affect the induction of status epilepticus and seizure-induced morphological changes

Genetic deficits have been discovered in human epilepsy, which lead to alteration of the balance between excitation and inhibition, and ultimately result in seizures. Rodents show similar genetic determinants of seizure induction. To test whether seizure‐prone phenotypes exhibit increased seizure‐related morphological changes, we compared two standard rat strains (Long–Evans hooded and Wistar) and two specially bred strains following status epilepticus. The special strains, namely the kindling‐prone (FAST) and kindling‐resistant (SLOW) strains, were selectively bred based on their amygdala kindling rate. Although the Wistar and Long–Evans hooded strains experienced similar amounts of seizure activity, Wistar rats showed greater mossy fiber sprouting and hilar neuronal loss than Long–Evans hooded rats. The mossy fiber system was affected differently in FAST and SLOW rats. FAST animals showed more mossy fiber granules in the naïve state, but were more resistant to seizure‐induced mossy fiber sprouting than SLOW rats. These properties of the FAST strain are consistent with those observed in juvenile animals, further supporting the hypothesis that the FAST strain shares circuit properties similar to those seen in immature animals. Furthermore, the extent of mossy fiber sprouting was not well correlated with sensitivity to status epilepticus, but was positively correlated with the frequency of spontaneous recurrent seizures in the FAST rats only, suggesting a possible role for axonal sprouting in the development of spontaneous seizures in these animals. We conclude that genetic factors clearly affect seizure development and related morphological changes in both standard laboratory strains and the selectively bred seizure‐prone and seizure‐resistant strains.     

Non-human primate models of childhood psychopathology: the promise and the limitations

Although non-human primate models have been used previously to investigate the neurobiology of several sensory and cognitive developmental pathologies, they have been employed only sparingly to study the etiology of childhood psychopathologies for which deficits in social behavior and emotion regulation are major symptoms. Previous investigations of both adult human and non-human primates have indicated that primate social behavior and emotion are regulated by a complex neural network, in which the amygdala and orbital frontal cortex play major roles. Therefore, this review will provide information generated from the study of macaque monkeys regarding the timing of normal social and emotional behavior development, the normal pattern of anatomical and functional maturation of the amygdala and orbital frontal cortex, as well as information regarding the neural and behavioral effects of early perturbations of these two neural structures. We will also highlight 'critical periods' of macaque development, during which major refinements in the behavioral repertoire appear to coincide with significant neural maturation of the amygdala and/or orbital frontal cortex. The identification of these 'critical periods' may allow one to better predict the specific behavioral impairments likely to appear after neonatal damage to one or both of these neural areas at different time points during development. This experimental approach may provide a new and important way to inform and stimulate research on childhood psychopathologies, such as autism, schizophrenia and Williams syndrome, in which the development of normal social skills and emotional regulation is severely perturbed. Finally, the promise and limitations inherent to the use of non-human primate models of childhood psychopathology will be discussed.     

Affective neuroscience and psychophysiology: toward a synthesis

This article reviews the author's program of research on the neural substrates of emotion and affective style and their behavioral and peripheral biological correlates. Two core dimensions along which affect is organized are approach and withdrawal. Some of the key circuitry underlying approach and withdrawal components of emotion is reviewed with an emphasis on the role played by different sectors of the prefrontal cortex (PFC) and amygdala. Affective style refers to individual differences in valence-specific features of emotional reactivity and regulation. The different parameters of affective style can be objectively measured using specific laboratory probes. Relations between individual differences in prefrontal and amygdala function and specific components of affective style are illustrated. The final section of the article concludes with a brief discussion of plasticity in the central circuitry of emotion and the possibility that this circuitry can be shaped by training experiences that might potentially promote a more resilient, positive affective style. The implications of this body of work for a broader conception of psychophysiology and for training the next generation of psychophysiologists are considered in the conclusion.     

Sex- and hemisphere-related influences on the neurobiology of emotionally influenced memory

Recent findings are beginning to reveal apparently pronounced influences of both sex and cerebral hemisphere on the neurobiology of emotionally influenced memory. In this article, I first provide a brief, general overview of sex-related influences on brain and cognition. I next describe recent findings from my laboratory and others demonstrating sex-related influences on neural mechanisms underlying emotionally influenced explicit recall of emotionally arousing events. Both the hemispheric involvement of the human amygdala in memory for emotionally arousing events and the impairing effect of β-adrenergic blockade on memory for emotional events, exhibit sex-related differences. I hypothesize that both of these effects relate to a modulatory influence of each amygdala on ipsilateral hemispheric function. Specifically, I hypothesize that the right hemisphere amygdala modulates right hemispheric processing of global/central aspects of a situation (an effect more pronounced in males), while the left hemisphere amygdala modulates left hemispheric processing of more local/fine detail aspects of a situation (an effect more pronounced in females). More generally, these findings presented here suggest that the interacting influences of sex and cerebral hemisphere on emotionally influenced memory are more pronounced than has been widely appreciated to date.     

Location of putative glutamatergic neurons projecting to the medial preoptic area of the rat hypothalamus

The medial preoptic area is a key structure in the neural control of reproduction. Considerable evidence has accumulated indicating that glutamatergic innervation of the area plays an important role in this control. Sources of the glutamatergic input are unknown. Present investigations were aimed at studying this question. [3H]D-aspartate, which is selectively taken up by high-affinity uptake sites at presynaptic endings that use glutamate or aspartate as a transmitter, and is transported back to the cell body, was injected into the medial preoptic area. The neurons retrogradely labelled with [3H]D-aspartate were detected autoradiographically. Labelled cells were found in several telencephalic and diencephalic structures, but not in the brainstem. Within the telencephalon, labelled neurons were detected in the lateral septum, bed nucleus of the stria terminalis and amygdala. Diencephalic structures included the medial preoptic area itself, hypothalamic paraventricular, suprachiasmatic, ventromedial, arcuate, ventral premammillary, supramammillary and thalamic paraventricular nuclei. All of them are known to project to this area. The findings provide the first neuromorphological data on the location of putative glutamatergic neurons projecting to the medial preoptic area. Furthermore, they indicate that local putative glutamatergic neurons as well as several telencephalic and diencephalic structures contribute to the glutamatergic innervation of the area.     

Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions.

The objective of this study was to determine if there are innate differences in gene expression in selected CNS regions between inbred alcohol-preferring (iP) and -non-preferring (iNP) rats. Gene expression was determined in the nucleus accumbens (ACB), amygdala (AMYG), frontal cortex (FC), caudate-putamen (CPU), and hippocampus (HIPP) of alcohol-na?ve adult male iP and iNP rats, using Affymetrix Rat Genome U34A microarrays (n = 6/strain). Using Linear Modeling for Microarray Analysis with a false discovery rate threshold of 0.1, there were 16 genes with differential expression in the ACB, 54 in the AMYG, 8 in the FC, 24 in the CPU, and 21 in the HIPP. When examining the main effect of strain across regions, 296 genes were differentially expressed. Although the relatively small number of genes found significant within individual regions precluded a powerful analysis for over-represented Gene Ontology categories, the much larger list resulting from the main effect of strain analysis produced 17 over-represented categories (P < .05), including axon guidance, gliogenesis, negative regulation of programmed cell death, regulation of programmed cell death, regulation of synapse structure function, and transmission of nerve impulse. Co-citation analysis and graphing of significant genes revealed a network involved in the neuropeptide Y (NPY) transmitter system. Correlation of all significant genes with those located within previously established rat alcohol QTLs revealed that of the total of 313 significant genes, 71 are located within such QTLs. The many regional and overall gene expression differences between the iP and iNP rat lines may contribute to the divergent alcohol drinking phenotypes of these rats.     

Small amygdala – high aggression? The role of the amygdala in modulating aggression in healthy subjects

Objective. Several lines of evidence suggest an association between the amygdala and the modulation of aggressive behaviour. Previous morphometric brain imaging studies have focused on the role of the amygdala in the context of pathologic neuropsychiatric conditions like depression, personality disorders, and dysphoric and aggressive behaviour in epilepsy. In order to better understand the physiological role of the amygdala in modulating aggressive behaviour we investigated the relationship between amygdala volumes and lifetime aggression in healthy subjects. Methods. Morphometric brain scans were obtained in 20 healthy volunteers. Amygdala volumes were measured by manually outlining the boundaries of the structure following a well established and validated protocol. Careful psychiatric and psychometric assessment was done to exclude any psychiatric disorder and to assess lifetime aggressiveness with an established and validated psychometric instrument (i.e. Life History of Aggression Assessment (LHA)). Results. All volunteers scored in the normal range of lifetime aggression. Volunteers with higher aggression scores displayed a 16–18% reduction of amygdala volumes. There was a highly significant negative correlation between amygdala volumes and trait aggression. Conclusion. The extent of volumetric differences in this study is remarkable and suggests that amygdala volumes might be a surrogate marker for the personality property of aggressiveness in healthy human beings.     

Structural plasticity of dentate granule cell mossy fibers during the development of limbic epilepsy

Altered granule cell≫CA3 pyramidal cell synaptic connectivity may contribute to the development of limbic epilepsy. To explore this possibility, granule cell giant mossy fiber bouton plasticity was examined in the kindling and pilocarpine models of epilepsy using green fluorescent protein‐expressing transgenic mice. These studies revealed significant increases in the frequency of giant boutons with satellite boutons 2 days and 1 month after pilocarpine status epilepticus, and increases in giant bouton area at 1 month. Similar increases in giant bouton area were observed shortly after kindling. Finally, both models exhibited plasticity of mossy fiber giant bouton filopodia, which contact GABAergic interneurons mediating feedforward inhibition of CA3 pyramids. In the kindling model, however, all changes were fleeting, having resolved by 1 month after the last evoked seizure. Together, these findings demonstrate striking structural plasticity of granule cell mossy fiber synaptic terminal structure in two distinct models of adult limbic epileptogenesis. We suggest that these plasticities modify local connectivities between individual mossy fiber terminals and their targets, inhibitory interneurons, and CA3 pyramidal cells potentially altering the balance of excitation and inhibition during the development of epilepsy. © 2009 Wiley‐Liss, Inc.     

Adaptation and habituation to an open field and responses to various stressful events in animals with neonatal lesions in the amygdala or ventral hippocampus

A rat model of neurodevelopmental psychopathological disorders, designed to determine neurodevelopmental deficits following damage to the brain early in life, was used to investigate behavioural changes in adaptation and habituation to an open field and responses to different kinds of stressful events. Animals with bilateral ibotenic acid lesions in the amygdala or ventral hippocampus on day 7 or 21 of life were compared to sham-operated animals. According to the model it was assumed that behavioural changes in animals lesioned on day 7, but not in animals lesioned on day 21 of life, were caused by maldevelopment of one or more structures connected to the damaged area. Animals lesioned in the amygdala or ventral hippocampus on day 7, but not animals lesioned in these structures on day 21 of life, displayed decreased (within-session) adaptation and (between-session) habituation to the open field and a decrease in immobility in the forced swim test, whereas only animals lesioned in the amygdala displayed enhanced general activity. These results were indicative of neurodevelopmental deficits. No changes in stress-induced hyperthermia were found, while animals lesioned in the amygdala both on day 7 or 21 of life exhibited decreased conditioned ultrasonic vocalizations. These latter results suggest that the amygdala is implicated in the conditioned stress-induced response. The contribution of the present findings to the animal model of neurodevelopmental disorders like schizophrenia and possible brain structures and neurotransmitter systems involved in the neurodevelopmental deficits are discussed.