Neural Reorganization Due to Neonatal Amygdala Lesions in the Rhesus Monkey: Changes in Morphology and Network Structure.

It is generally believed that neural damage that occurs early in development is associated with greater adaptive capacity relative to similar damage in an older individual. However, few studies have surveyed whole brain changes following early focal damage. In this report, we employed multimodal magnetic resonance imaging analyses of adult rhesus macaque monkeys who had previously undergone bilateral, neurotoxic lesions of the amygdala at about 2 weeks of age. A deformation-based morphometric approach demonstrated reduction of the volumes of the anterior temporal lobe, anterior commissure, basal ganglia, and pulvinar in animals with early amygdala lesions compared to controls. In contrast, animals with early amygdala lesions had an enlarged cingulate cortex, medial superior frontal gyrus, and medial parietal cortex. Diffusion-weighted imaging tractography and network analysis were also used to compare connectivity patterns and higher-level measures of communication across the brain. Using the communicability metric, which integrates direct and indirect paths between regions, lesioned animals showed extensive degradation of network integrity in the temporal and orbitofrontal cortices. This work demonstrates both degenerative as well as progressive large-scale neural changes following long-term recovery from neonatal focal brain damage.

Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

The expression of social dominance following neonatal lesions of the amygdala or hippocampus in rhesus monkeys (Macaca mulatta).

As part of ongoing studies on the neurobiology of socioemotional behavior in the nonhuman primate, the authors examined the social dominance hierarchy of juvenile macaque monkeys (Macaca mulatta) that received bilateral ibotenic acid lesions of the amygdala or the hippocampus or a sham surgical procedure at 2 weeks of age. The subjects were reared by their mothers with daily access to large social groups. Behavioral observations were conducted while monkeys were given access to a limited preferred food. This testing situation reliably elicited numerous species-typical dominance behaviors. All subjects were motivated to retrieve the food when tested individually. However, when a group of 6 monkeys was given access to only 1 container of the preferred food, the amygdala-lesioned monkeys had less frequent initial access to the food, had longer latencies to obtain the food, and demonstrated fewer species-typical aggressive behaviors. They were thus lower ranking on all indices of social dominance. The authors discuss these findings in relation to the role of the amygdala in the establishment of social rank and the regulation of aggression and fear.

Morphological characteristics and electrophysiological properties of CA1 pyramidal neurons in macaque monkeys.

Little is known about the morphological characteristics and intrinsic electrophysiological properties of individual neurons in the nonhuman primate hippocampus. We have used intracellular recording and biocytin-labeling techniques in the in vitro hippocampal slice preparation to provide quantitative evaluation of the fundamental morphological and intrinsic electrophysiological characteristics of macaque monkey CA1 pyramidal neurons. These neurons have previously been studied in the rat in our laboratory. Monkey CA1 pyramidal neurons have an average soma volume of 3578 microm3, 4.71 basal dendrites with 53 terminal branches for a dendritic length of about 10,164 microm, 1.13 apical dendrites with 47 terminal branches for a dendritic length of about 10,678 microm. In comparison, rat CA1 pyramidal neurons have an average soma volume of 2066 microm3, 3.35 basal dendrites with 29 terminal branches for a dendritic length of about 4,586 microm, 1.43 apical dendrites with 62 terminal branches for a dendritic length of about 8,838 microm. The basic intrinsic electrophysiological properties of CA1 pyramidal cells are similar in monkeys and rats. Monkey CA1 pyramidal neurons have a resting membrane potential of about -62 mV (rat: -62 mV), an input resistance of 35 MOmega (rat: 34-49 MOmega), a rheobase of 0.17 nA (rat: 0.12-0.20 nA) and an action potential amplitude of 83 mV (rat: 71-89 mV). Although morphological differences such as the increased dendritic length may translate into differences in neural processing between primates and rodents, the functional significance of these morphological differences is not yet clear. Quantitative studies of the primate brain are critical in order to extrapolate information derived from rodent studies into better understanding of the normal and pathological function of the human hippocampus.

The development of social behavior following neonatal amygdala lesions in rhesus monkeys.

We examined the role of the amygdala in the development of nonhuman primate social behavior. Twenty-four rhesus monkeys received bilateral ibotenic acid lesions of either the amygdala or the hippocampus or received a sham surgical procedure at 2 weeks of age. Subjects were reared with their mothers and were provided daily access to social rearing cohorts. The subjects were weaned at 6 months of age and then observed while paired with familiar conspecifics at 6 and 9 months of age and with unfamiliar conspecifics at 1 year of age. The subjects were also observed during daily cohort socialization periods. Neither amygdala nor hippocampus lesions altered fundamental aspects of social behavior development. All subjects, regardless of lesion condition, developed a species-typical repertoire of social behavior and displayed interest in conspecifics during social encounters. The amygdala lesions, however, clearly affected behaviors related to fear processing. The amygdala-lesioned subjects produced more fear behaviors during social encounters than did control or hippocampus-lesioned subjects. Although the heightened fear response of the amygdala-lesioned subjects was consistent across different testing paradigms and was observed with both familiar and novel partners, it did not preclude social interactions. In fact, the amygdala-lesioned subjects displayed particular social behaviors, such as following, cooing, grunting, presenting to be groomed, and presenting to be mounted more frequently than either control or hippocampus-lesioned subjects. These findings are consistent with the view that the amygdala is not needed to develop fundamental aspects of social behavior and may be more related to the detection and avoidance of environmental dangers.

The development of mother-infant interactions after neonatal amygdala lesions in rhesus monkeys.

As part of ongoing studies on the neurobiology of socioemotional behavior in the nonhuman primate, we examined the development of mother-infant interactions in 24 macaque monkeys who received either bilateral amygdala or hippocampus ibotenic acid lesions, or a sham surgical procedure at 2 weeks of age. After surgery, the infants were returned to their mothers and reared with daily access to small social groups. Behavioral observations of the infants in dyads (mother-infant pairs alone), tetrads (two mother-infant pairs), and social groups (six mother-infant pairs and one adult male) revealed species-typical mother-infant interactions for all lesion conditions, with the exception of increased physical contact time between the amygdala-lesioned infants and their mothers. Immediately after permanent separation from their mothers at 6 months of age, the infants were tested in a mother preference test that allowed the infants to choose between their mother and another familiar adult female. Unlike control and hippocampus-lesioned infants, the amygdala-lesioned infants did not preferentially seek proximity to their mother, nor did they produce distress vocalizations. Given the normal development of mother-infant interactions observed before weaning, we attribute the behavior of the amygdala-lesioned infants during the preference test to an impaired ability to perceive potential danger (i.e., separation from their mother in a novel environment), rather than to a disruption of the mother-infant relationship. These results are consistent with the view that the amygdala is not essential for fundamental aspects of social behavior but is necessary to evaluate potentially dangerous situations and to coordinate appropriate behavioral responses.

Changes in spatial memory mediated by experimental variation in food supply do not affect hippocampal anatomy in mountain chickadees (Poecile gambeli).

Earlier reports suggested that seasonal variation in food-caching behavior (caching intensity and cache retrieval accuracy) might correlate with morphological changes in the hippocampal formation, a brain structure thought to play a role in remembering cache locations. We demonstrated that changes in cache retrieval accuracy can also be triggered by experimental variation in food supply: captive mountain chickadees (Poecile gambeli) maintained on limited and unpredictable food supply were more accurate at recovering their caches and performed better on spatial memory tests than birds maintained on ad libitum food. In this study, we investigated whether these two treatment groups also differed in the volume and neuron number of the hippocampal formation. If variation in memory for food caches correlates with hippocampal size, then our birds with enhanced cache recovery and spatial memory performance should have larger hippocampal volumes and total neuron numbers. Contrary to this prediction we found no significant differences in volume or total neuron number of the hippocampal formation between the two treatment groups. Our results therefore indicate that changes in food-caching behavior and spatial memory performance, as mediated by experimental variations in food supply, are not necessarily accompanied by morphological changes in volume or neuron number of the hippocampal formation in fully developed, experienced food-caching birds.

Increased social fear and decreased fear of objects in monkeys with neonatal amygdala lesions.

The amygdala has been implicated in the mediation of emotional and species-specific social behavior (Kling et al., 1970; Kling and Brothers, 1992; Kluver and Bucy, 1939; Rosvold et al., 1954). Humans with bilateral amygdala damage are impaired in judging negative emotion in facial expressions and making accurate judgements of trustworthiness (Adolphs et al., 1998, 1994). Amygdala dysfunction has also been implicated in human disorders ranging from social anxiety (Birbaumer et al., 1998) to depression (Drevets, 2000) to autism (Bachevalier, 1994; Baron-Cohen et al., 2000; Bauman and Kemper, 1993). We produced selective amygdala lesions in 2-week-old macaque monkeys who were returned to their mothers for rearing. At 6-8 months of age, the lesioned animals demonstrated less fear of novel objects such as rubber snakes than age-matched controls. However, they displayed substantially more fear behavior than controls during dyadic social interactions. These results suggest that neonatal amygdala lesions dissociate a system that mediates social fear from one that mediates fear of inanimate objects. Furthermore, much of the age-appropriate repertoire of social behavior was present in amygdala-lesioned infants indicating that these lesions do not produce autistic-like behavior in monkeys. Finally, amygdala lesions early in development have different effects on social behavior than lesions produced in adulthood.

Hippocampal-neocortical interaction: a hierarchy of associativity.

The structures forming the medial temporal lobe appear to be necessary for the establishment of long-term declarative memory. In particular, they may be involved in the "consolidation" of information in higher-order associational cortices, perhaps through feedback projections. This review highlights the fact that the medial temporal lobe is organized as a hierarchy of associational networks. Indeed, associational connections within the perirhinal, parahippocampal, and entorhinal cortices enables a significant amount of integration of unimodal and polymodal inputs, so that only highly integrated information reaches the remainder of the hippocampal formation. The feedback efferent projections from the perirhinal and parahippocampal cortices to the neocortex largely reciprocate the afferent projections from the neocortex to these areas. There are, however, noticeable differences in the degree of reciprocity of connections between the perirhinal and parahippocampal cortices and certain areas of the neocortex, in particular in the frontal and temporal lobes. These observations are particularly important for models of hippocampal-neocortical interaction and long-term storage of information in the neocortex. Furthermore, recent functional studies suggest that the perirhinal and parahippocampal cortices are more than interfaces for communication between the neocortex and the hippocampal formation. These structures participate actively in memory processes, but the precise role they play in the service of memory or other cognitive functions is currently unclear.

Sex differences, but no seasonal variations in the hippocampus of food-caching squirrels: a stereological study.

Recent studies have described sex differences in the relative size of the hippocampus that are associated with sex differences in space use in birds and short-lived mammals. A correlation between spatial learning and increased hippocampal volume has also been demonstrated in food-caching animals. Such results suggest that sexually dimorphic spatial learning (sex differences in space use during the breeding season) and seasonal variations in food-caching behavior (spatial memory for cache locations) might correlate with morphological changes in the hippocampus of adult long-lived mammals. We used modern stereological techniques to examine the volume and neuron number of the structures forming the hippocampal complex (dentate gyrus, CA3, and CA1) of wild adult eastern gray squirrels (Sciurus carolinensis) throughout the year. We observed differences in brain size between samples collected at different times of the year (October, January, and June). Our analysis showed sex differences, but no seasonal variations, in the volume of CA1 stratum oriens and stratum radiatum. There were no sex differences or seasonal variations in the relative volume or the number of neurons of any other layer of the structures forming the hippocampal complex. These results confirm the existence of sex differences in the structure of the hippocampus; however, this sexual dimorphism does not vary seasonally in adulthood and is likely to result from developmental processes. These results do not support the hypothesis that seasonal variations in food-caching behavior might correlate with morphological changes, such as variations in volume or neuron number, in the hippocampal complex of adult long-lived mammals.

Lesions in the budgerigar vocal control nucleus NLc affect production, but not memory, of english words and natural vocalizations.

This study investigates the role of the psittacid (parrot) central nucleus of the lateral neostriatum (NLc) in the production of learned English and natural vocalizations. Anatomic data have led researchers to define NLc alternately as the parrot homologue (Paton et al. [1981] J Neurosci. 11:1279-1288) or analogue (Striedter [1994] J Comp Neurol. 343:35-56) of the songbird high vocal center. Although numerous functional and electrophysiological studies have identified the role of various songbird vocal control nuclei, few similar functional studies have been performed in parrots, particularly with respect to NLc. In this study, both novel behavioral techniques and precise neurochemical lesions have been used to investigate the role of NLc in the production of learned vocalizations. The results suggest that NLc is involved in the production of, but not memory for, learned English and natural vocalizations. Specifically, NLc lesions disrupted the amplitude of amplitude-modulated vocalizations, but did not affect the frequency of the dominant or carrier signal of these vocalizations. These data provide some of the first evidence for the functional role of a parrot vocal control nucleus.

The seasonal pattern of cell proliferation and neuron number in the dentate gyrus of wild adult eastern grey squirrels.

The dentate gyrus is one of two areas in the mammalian brain that produces neurons in adulthood. Neurogenesis (proliferation, survival, and differentiation of new neurons) is regulated by experience, and increased neurogenesis appears to be correlated with improved spatial learning in mammals and birds. We tested the hypothesis that in long-lived mammals that scatter-hoard food, seasonal variations in spatial memory processing (i.e. increased processing during caching season in the autumn) might correlate with changes in neurogenesis and neuron number in the granule cell layer of the dentate gyrus (gcl DG). We investigated the rate of cell proliferation and the total number of neurons in the granule cell layer of wild adult eastern grey squirrels (Sciurus carolinensis) at three different times of the year (October, January and June). We found no seasonal differences in cell proliferation rate or in total neuron number in the granule cell layer. Our findings are in agreement with those of previous studies in laboratory mice and rats, and in free-ranging, food-caching, black-capped chickadees, as well as with current hypotheses regarding the relationship between neurogenesis and learning. Our results, however, are also in agreement with the hypothesis that neurogenesis in the dentate gyrus represents a maintenance system that may be regulated by environmental factors, and that changes in total neuron number previously reported in rodents represent developmental changes rather than adult plasticity. The patterns observed in mature wild rodents, such as free-ranging squirrels, may represent more accurately the extent of hippocampal plasticity in adult mammals.

Vocal production mechanisms in the budgerigar (Melopsittacus undulatus): the presence and implications of amplitude modulation.

In this paper acoustic evidence is presented for the presence of amplitude modulation in budgerigar (Melopsittacus undulatus) contact calls and learned English vocalizations. Previously, acoustic analyses of budgerigar vocalizations have consisted solely of visual inspection of spectrograms or power spectra (derived from Fourier transformation). Such analyses have led researchers to conclude that budgerigar vocalizations are primarily frequency-modulated, harmonic vocalizations. Although budgerigar calls have been shown to contain regions that are modulated in amplitude, the implications of this fact have been largely ignored. Amplitude modulation, the nonlinear interaction between two separate signals that results in the creation of new, heterodyne (sum and difference) frequencies, can produce a very complex Fourier spectrum that may resemble that produced by a harmonic vocalization. In this paper, the acoustic principles necessary for identifying amplitude modulation present in signals are outlined, and followed by data demonstrating that amplitude modulation is a prominent feature not only of natural budgerigar contact calls, but also of their learned English vocalizations. It is illustrated how analyzing a vocalization that contains amplitude modulation as if it were harmonic can result in misinterpretations of the acoustic and physical properties of the sound and sound source. The implications of amplitude modulation for studies of the ontogenetic, physical, and neural basis of budgerigar vocalizations are discussed, and a potential model for how the budgerigar syrinx may function to produce amplitude modulation is proposed.

Olfactory traces and spatial learning in rats.

We conducted an experiment to assess the use of olfactory traces for spatial orientation in an open environment in rats, Rattus norvegicus. We trained rats to locate a food source at a fixed location from different starting points, in the presence or absence of visual information. A single food source was hidden in an array of 19 petri dishes regularly arranged in an open-field arena. Rats were trained to locate the food source either in white light (with full access to distant visuospatial information) or in darkness (without any visual information). In both cases, the goal was in a fixed location relative to the spatial frame of reference. The results of this experiment revealed that the presence of noncontrolled olfactory traces coherent with the spatial frame of reference enables rats to locate a unique position as accurately in darkness as with full access to visuospatial information. We hypothesize that the olfactory traces complement the use of other orientation mechanisms, such as path integration or the reliance on visuospatial information. This experiment demonstrates that rats can rely on olfactory traces for accurate orientation, and raises questions about the establishment of such traces in the absence of any other orientation mechanism. Copyright 1998 The Association for the Study of Animal Behaviour.

Olfactory cues potentiate learning of distant visuospatial information.

The influence of proximal olfactory cues on place learning and memory was tested in two different spatial tasks. Rats were trained to find a hole leading to their home cage or a single food source in an array of petri dishes. The two apparatuses differed both by the type of reinforcement (return to the home cage or food reward) and the local characteristics of the goal (masked holes or salient dishes). In both cases, the goal was in a fixed location relative to distant visual landmarks and could be marked by a local olfactory cue. Thus, the position of the goal was defined by two sets of redundant cues, each of which was sufficient to allow the discrimination of the goal location. These experiments were conducted with two strains of hooded rats (Long-Evans and PVG), which show different speeds of acquisition in place learning tasks. They revealed that the presence of an olfactory cue marking the goal facilitated learning of its location and that the facilitation persisted after the removal of the cue. Thus, the proximal olfactory cue appeared to potentiate learning and memory of the goal location relative to distant environmental cues. This facilitating effect was only detected when the expression of spatial memory was not already optimal, i.e., during the early phase of acquisition. It was not limited to a particular strain.

Integration of olfactory information in a spatial representation enabling accurate arm choice in the radial arm maze.

The aim of the present study was to determine whether and how rats can use local olfactory cues for spatial orientation. Rats were trained in an eight-arm radial maze under different conditions as defined by the presence or absence of supplementary olfactory cues marking each arm, the availability of distant visuospatial information, and the illumination of the maze (light or darkness). The different visual conditions were designed to dissociate among the effects of light per se and those of visuospatial cues, on the use of olfactory cues for accurate arm choice. Different procedures with modifications of the arrangement of olfactory cues were used to determine if rats formed a representation of the spatial configuration of the olfactory cues and if they could rely on such a representation for accurate arm choice in the radial maze. The present study demonstrated that the use of olfactory cues to direct arm choice in the radial arm maze was critically dependent on the illumination conditions and implied two different modes of processing of olfactory information according to the presence or the absence of light. Olfactory cues were used in an explicit manner and enabled accurate arm choice only in the absence of light. Rats, however, had an implicit memory of the location of the olfactory cues and formed a representation of the spatial position of these cues, whatever the lighting conditions. They did not memorize the spatial configuration of the olfactory cues per se but needed these cues to be linked to the external spatial frame of reference.

Influence of local environmental olfactory cues on place learning in rats.

The aim of the present study was to assess the influence of local environmental olfactory cues on place learning in rats. We developed a new experimental design allowing the comparison of the use of local olfactory and visual cues in spatial and discrimination learning. We compared the effect of both types of cues on the discrimination of a single food source in an open-field arena. The goal was either in a fixed or in a variable location, and could be indicated by local olfactory and/or visual cues. The local cues enhanced the discrimination of the goal dish, whether it was in a fixed or in a variable location. However, we did not observe any overshadowing of the spatial information by the local olfactory or visual cue. Rats relied primarily on distant visuospatial information to locate the goal, neglecting local information when it was in conflict with the spatial information.