The Development of Socially Directed Attention: An Functional Magnetic Resonance Imaging Study in Infant Monkeys.

Socially guided visual attention, such as gaze following and joint attention, represents the building block of higher-level social cognition in primates, although their neurodevelopmental processes are still poorly understood. Atypical development of these social skills has served as early marker of autism spectrum disorder and Williams syndrome. In this study, we trace the developmental trajectories of four neural networks underlying visual and attentional social engagement in the translational rhesus monkey model. Resting-state fMRI (rs-fMRI) data and gaze following skills were collected in infant rhesus macaques from birth through 6 months of age. Developmental trajectories from subjects with both resting-state fMRI and eye-tracking data were used to explore brain-behavior relationships. Our findings indicate robust increases in functional connectivity (FC) between primary visual areas (primary visual cortex [V1] - extrastriate area 3 [V3] and V3 - middle temporal area, ventral motion areas middle temporal area - AST, as well as between TE and amygdala (AMY) as infants mature. Significant FC decreases were found in more rostral areas of the pathways, such as areas temporal area occipital part - TE in the ventral object pathway, V3 - lateral intraparietal (LIP) of the dorsal visual attention pathway and V3 - temporo-parietal area of the ventral attention pathway. No changes in FC were found between cortical areas LIP-FEF and temporo-parietal area - Area 12 of the dorsal and ventral attention pathways or between AST-AMY and AMY-insula. Developmental trajectory of gaze following revealed a period of dynamic changes with gradual increases from 1 to 2 months, followed by slight decreases from 3 to 6 months. Exploratory association findings across the 6-month period showed that infants with higher gaze following had lower FC between primary visual areas V1-V3, but higher FC in the dorsal attention areas V3-LIP, both in the right hemisphere. Together, the first 6 months of life in rhesus macaques represent a critical period for the emergence of gaze following skills associated with maturational changes in FC of socially guided attention pathways.

Nonhuman primate models of hippocampal development and dysfunction.

Nonhuman primates provide highly valuable animal models that have significantly advanced our understanding of numerous behavioral and biological phenomena in humans. Here, we reviewed a series of developmental neuropsychological studies that informed us on the timing of development of the hippocampus and of hippocampal-dependent cognitive functions in primates. Data indicate that, in primates, the emergence of adult-like proficiency on behavioral tasks sensitive to hippocampal dysfunction is a stepwise process and reflects the gradual maturation of different hippocampal circuits and their connections with other neural structures. Profound and persistent memory loss resulting from insult to the hippocampus in infancy was absent in early infancy but became evident later in childhood and persisted in adulthood, indicating very little sparing or recovery of function. Finally, the early hippocampal insult resulted in both adaptive and maladaptive neuroplasticity: i.e., sparing contextual memory, but affecting working memory processes as well as emotional reactivity and hypothalamic-pituitary-adrenal (HPA) axis functioning. The results provide significant information on the emergence of hippocampal-dependent functions in humans, on the time course of memory impairment in human cases with early hippocampal insult, and on the clinical implication of the hippocampus in developmental neuropsychiatric disorders.

Altered hippocampal-prefrontal functional network integrity in adult macaque monkeys with neonatal hippocampal lesions.

The dorsolateral prefrontal cortex (DLPFC) and ventral lateral prefrontal cortex (VLPFC) play critical but different roles in working memory (WM) processes. Resting-state functional MRI (rs-fMRI) was employed to investigate the effects of neonatal hippocampal lesions on the functional connectivity (FC) between the hippocampus (H) and the DLPFC and VLPFC and its relation to WM performance in adult monkeys. Adult rhesus monkeys with neonatal H lesions (Neo-H, n = 5) and age- and gender-matched sham-operated monkeys (Neo-C, n = 5) were scanned around 10 years of age. The FC of H-DLPFC and H-VLPFC in Neo-H monkeys was significantly altered as compared to controls, but also switched from being positive in the Neo-C to negative in the Neo-H. In addition, the altered magnitude of FC between right H and bilateral DLPFC was significantly associated with the extent of the hippocampal lesions. In particular, the effects of neonatal hippocampal lesion on FC appeared to be selective to the left hemisphere of the brain (i.e. asymmetric in the two hemispheres). Finally, FC between H and DLPFC correlated with WM task performance on the SU-DNMS and the Obj-SO tasks for the control animals, but only with the H-VLPFC and SU-DNMS task for the Neo-H animals. In conclusion, the present rsfMRI study revealed that the neonatal hippocampal lesions significantly but differently altered the integrity in the functional connectivity of H-DLPFC and H-VLPFC. The similarities between the behavioral, cognitive and neural alterations in Neo-H monkeys and Schizophrenia (SZ) patients provide a strong translational model to develop new therapeutic tools for SZ.

Rhesus Macaque Brain Developmental Trajectory: A Longitudinal Analysis Using Tensor-Based Structural Morphometry and Diffusion Tensor Imaging.

The typical developmental trajectory of brain structure among nonhuman primates (NHPs) remains poorly understood. In this study, we characterized the normative trajectory of developmental change among a cohort of rhesus monkeys (n = 28), ranging in age from 2 to 22 months, using structural MRI datasets that were longitudinally acquired every 3-4 months. We hypothesized that NHP-specific transient intracranial volume decreases reported during late infancy would be part of the typical developmental process, which is driven by volumetric contraction of gray matter in primary functional areas. To this end, we performed multiscale analyses from the whole brain to voxel level, characterizing regional heterogeneity, hemispheric asymmetry, and sexual dimorphism in developmental patterns. The longitudinal trajectory of brain development was explained by three different regional volumetric growth patterns (exponentially decreasing, undulating, and linearly increasing), which resulted in developmental brain volume curves with transient brain volumetric decreases. White matter (WM) fractional anisotropy increased with age, corresponding to WM volume increases, while mean diffusivity (MD) showed biphasic patterns. The longitudinal trajectory of brain development in young rhesus monkeys follows typical maturation patterns seen in humans, but regional volumetric and MD changes are more dynamic in rhesus monkeys compared with humans, with marked decreases followed by "rebound-like" increases.

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series.

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

Diffusion tensor imaging reveals microstructural alterations in corpus callosum and associated transcallosal fiber tracts in adult macaques with neonatal hippocampal lesions.

To investigate the effects of neonatal hippocampal lesions on the microstructural integrity of the corpus callosum (CC) in adulthood, macaque monkeys (n = 5) with neonatal bilateral neurotoxic hippocampal lesion (Neo-Hibo) and sham-operated controls (Neo-C, n = 5) were scanned using magnetic resonance diffusion tensor imaging (DTI) technique at 8-10 years old. CC was segmented into seven regionsgrouped into anterior CC (rostrum, genu, rostral body and anterior midbody) and posterior CC (posterior midbody, isthmus and splenium) for data analysis. Associated transcallosal fiber tracts were delineated using probabilistic tractography and evaluated with tract-based spatial statistics (TBSS). Neo-Hibo lesions resulted in significant increased diffusivity indices (mean, axial and radial diffusivity) in CC posterior segments. Also, significant decreased fractional anisotropy (FA) and increased diffusivity indices were seen in the associated transcallosal fiber tracts proximal to motor, posterior parietal and retrosplenial cortices. In Neo-Hibo animals, increased mean diffusivity (MD) in posterior midbody negatively correlated with reduction of CC surface areaand the magnitude of their memory impairments was significantly correlated with FA in transcallosal fiber tracts across splenium. Although no microstructural changes were observed in CC anterior segments, changes in FA values and diffusivity indices were observed in the white matter fibers of the ventromedial prefrontal cortex. Thus, Neo-H lesions resulted in enduring degradation in transcallosal fibers proximal to parietal and retrosplenial cortices, and hemispheric connections through posterior CC. The findings may provide complementary information for understanding the neural substrate of behavioral and cognitive deficits observed in patients with early insult to the hippocampus.

Effects of Separate or Combined Neonatal Damage to the Orbital Frontal Cortex and the Inferior Convexity on Object Recognition in Monkeys.

Unlike adult damage, neonatal damage to the inferior prefrontal convexity (IC) in monkeys spares learning and performance on the delayed nonmatching-to-sample (DNMS) task ( Málková et al. 2000). We investigated whether this sparing was due to compensation by undamaged orbital frontal cortex (O), an area also critical for DNMS, by comparing combined IC and O damage (Neo-ICO) with damage to O alone (Neo-O). Group Neo-ICO was impaired on DNMS learning at 3 months and 2 years of age. In contrast, Group Neo-O was impaired at 3 months, but recovered this function by 2 years, compared with Neo-IC and controls (N). We propose that the intact IC assumed the function of learning the DNMS rule for Group Neo-O. The persistent impairment after Neo-ICO lesions suggests that whereas O may likely support the rule acquisition in the absence of IC, no compensatory mechanisms are available after the combined damage. For the memory of lists of items, all groups were impaired at 3 months. At 2 years, the performance of Groups N and Neo-IC dramatically improved, whereas that of groups with O damage (Neo-O and Neo-ICO) remained impaired, indicating a critical role for O in recognition memory that cannot be substituted by another area.

An MRI study of the corpus callosum in monkeys: Developmental trajectories and effects of neonatal hippocampal and amygdala lesions.

This study provides the first characterization of early developmental trajectories of corpus callosum (CC) segments in rhesus macaques using noninvasive MRI techniques and assesses long-term effects of neonatal amygdala or hippocampal lesions on CC morphometry. In Experiment 1, 10 monkeys (5 males) were scanned at 1 week-2 years of age; eight additional infants (4 males) were scanned once at 1-4 weeks of age. The first 8 months showed marked growth across all segments, with sustained, albeit slower, growth through 24 months. Males and females had comparable patterns of CC maturation overall, but exhibited slight differences in the anterior and posterior segments, with greater increases in the isthmus for males and greater increases in the rostrum for females. The developmental changes are likely a consequence of varying degrees of axonal myelination, redirection, and pruning. In Experiment 2, animals with neonatal lesions of the amygdala (n = 6; 3 males) or hippocampus (n = 6; 4 males) were scanned at 1.5 years post-surgery and compared to scans of six control animals from Experiment 1. Whereas amygdala damage yielded larger rostral and posterior body segments, hippocampal damage yielded larger rostrum and isthmus. These differences demonstrate that early perturbations to one medial temporal lobe structure may produce extensive and long-lasting repercussions in other brain areas. The current findings emphasize the complexity of neural circuitry putatively subserving neurodevelopmental disorders such as autism spectrum disorder and Williams syndrome, which are each characterized by malformations and dysfunction of complex neural networks that include regions of the medial temporal lobe.

Decreased functional connectivity in dorsolateral prefrontal cortical networks in adult macaques with neonatal hippocampal lesions: Relations to visual working memory deficits.

Neonatal hippocampal lesions in monkeys impairs normal performance on both relational and working memory tasks, suggesting that the early lesions have impacted the normal development of prefrontal-hippocampal functional interactions necessary for normal performance on these tasks. Given that working memory processes engage distributed neuronal networks associated with the prefrontal cortex, it is critical to explore the integrity of distributed neural networks of dorsolateral prefrontal cortex (dlPFC) following neonatal hippocampal lesions in monkeys. We used resting-state functional MRI to assess functional connectivity of dlPFC networks in monkeys with neonatal neurotoxic hippocampal lesion (Neo-Hibo, n=4) and sham-operated control animals (Neo-C, n=4). Significant differences in the patterns of dlPFC functional networks were found between Groups Neo-Hibo and Neo-C. The within-group maps and the between-group comparisons yielded a highly coherent picture showing altered interactions of core regions of the working memory network (medial prefrontal cortex and posterior parietal cortex) as well as the dorsal (fundus of superior temporal area and superior temporal cortex) and ventral (V4 and infero-temporal cortex) visual processing areas in animals with Neo-Hibo lesions. Correlations between functional connectivity changes and working memory impairment in the same animals were found only between the dlPFC and visual cortical areas (V4 and infero-temporal cortex). Thus, the impact of the neonatal hippocampal lesions extends to multiple cortical areas interconnected with the dlPFC.

Neonatal amygdala lesions lead to increased activity of brain CRF systems and hypothalamic-pituitary-adrenal axis of juvenile rhesus monkeys.

The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on "developmental switches" in amygdala function and connectivity with other brain areas.

Alterations of hippocampal projections in adult macaques with neonatal hippocampal lesions: a Diffusion Tensor Imaging study.

Neuropsychological and brain imaging studies have demonstrated persistent deficits in memory functions and structural changes after neonatal neurotoxic hippocampal lesion in monkeys. However, the relevant microstructural changes in the white matter of affected brain regions following this early insult remain unknown. This study assessed white matter integrity in the main hippocampal projections of adult macaque monkeys with neonatal hippocampal lesions, using diffusion tensor imaging (DTI). Data analysis was performed using tract-based spatial statistics (TBSS) and compared with volume of interest statistics. Alterations of fractional anisotropy (FA) and diffusivity indices were observed in fornix, temporal stem, ventromedial prefrontal cortex and optical radiations. To further validate the lesion effects on the prefrontal cortex, probabilistic diffusion tractography was used to examine the integrity of the fiber connections between hippocampus and ventromedial prefrontal cortex, and alterations were found in these connections. In addition, increased radial diffusivity in the left ventromedial prefrontal cortex correlated negatively with the severity of deficits in working memory in the same monkeys. The findings revealed microstructural changes due to neonatal hippocampal lesion, and confirmed that neonatal neurotoxic hippocampal lesions resulted in significant and enduring functional alterations in the hippocampal projection system.

A two years longitudinal study of a transgenic Huntington disease monkey.

BACKGROUND: A two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington's disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements. RESULTS: Changes in striatal and hippocampal volumes in rHD1 were observed with progressive impairment in motor functions and cognitive decline, including deficits in learning stimulus-reward associations, recognition memory and spatial memory. The results demonstrate a progressive cognitive decline and morphometric changes in the striatum and hippocampus in a transgenic HD monkey. CONCLUSIONS: This is the first study on a primate model of human HD based on longitudinal clinical measurements. While this study is based a single HD monkey, an ongoing longitudinal study with additional HD monkeys will be important for the confirmation of our findings. A nonhuman primate model of HD could complement other animal models of HD to better understand the pathogenesis of HD and future development of diagnostics and therapeutics through longitudinal assessment.

Towards a transgenic model of Huntington's disease in a non-human primate.

Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.

Mother recognition and preference after neonatal amygdala lesions in rhesus macaques (Macaca mulatta) raised in a semi-naturalistic environment.

Attachment to the caregiver, typically the biological mother, is crucial to young mammals' socio-emotional development. Although studies in nonprimate species suggest that the amygdala regulates social preference and attachment development, its role in primate filial attachment development has been little investigated and has produced mixed results. This study assessed the effects of neonatal amygdala- (Neo-A, N = 16) and sham- (Neo-C, N = 12) lesions on mother recognition and discrimination in macaques raised in species-typical social groups. Neonatal amygdalectomy did not affect social discriminative abilities and mother preference at 3 and 6 months of age, strongly suggesting that the amygdala is not involved in the cognitive processes underlying the development of filial attachment at least when the amygdala damage occurred after the third to fourth weeks of age. Nevertheless, as compared to sham-operated controls, amygdalectomized infants initiated physical contact with their mothers less frequently. The findings are discussed in relation to the known contribution of the amygdala to filial attachment in both rodents and humans.

Neonatal amygdala lesions alter mother-infant interactions in rhesus monkeys living in a species-typical social environment.

The current study examined the effects of neonatal amygdala lesions on mother-infant interactions in rhesus monkeys reared in large species-typical social groups. Focal observations of mother-infant interactions were collected in their social group for the first 12 months postpartum on infants that had received amygdala lesions (Neo-A) at 24-25 days of age and control infants. Early amygdala lesions resulted in subtle behavioral alterations. Neo-A females exhibited earlier emergence of independence from the mother than did control females, spending more time away from their mother, whereas Neo-A males did not. Also, a set of behaviors, including coo vocalizations, time in contact, and time away from the mother, accurately discriminated Neo-A females from control females, but not Neo-A and control males. Data suggest that neonatal amygdalectomy either reduced fear, therefore increasing exploration in females, or reduced the positive reward value of maternal contact. Unlike females, neonatal amygdala lesions had little measurable effects on male mother-infant interactions. The source of this sex difference is unknown.

Episodic memory development: Bridging animal and human research.

Human episodic memory is not functionally evident until about 2 years of age and continues to develop into the school years. Behavioral studies have elucidated this developmental timeline and its constituent processes. In tandem, lesion and neurophysiological studies in non-human primates and rodents have identified key neural substrates and circuit mechanisms that may underlie episodic memory development. Despite this progress, collaborative efforts between psychologists and neuroscientists remain limited, hindering progress. Here, we seek to bridge human and non-human episodic memory development research by offering a comparative review of studies using humans, non-human primates, and rodents. We highlight critical theoretical and methodological issues that limit cross-fertilization and propose a common research framework, adaptable to different species, that may facilitate cross-species research endeavors.

Long-term effects of neonatal hippocampal lesions on novelty preference in monkeys.

In a recent longitudinal study to assess the development of incidental recognition memory processes in monkeys, we showed that the effects of neonatal hippocampal lesions did alter incidental recognition memory only when the animals reached the juvenile period (Zeamer et al., ). The current follow-up study tested whether this incidental memory loss was long-lasting, i.e., present in adulthood, or only transitory, due to functional compensation with further brain maturation. The same animals with neonatal hippocampal lesions and their sham-operated controls were re-tested in the visual paired-comparison task when they reached adulthood (48 months). The results demonstrated that, at least for easily discriminable color pictures of objects, the involvement of the hippocampus was only transitory, given that when re-tested as adults, animals with neonatal hippocampal lesions performed as well as sham-operated controls at all delays. Yet, significant recognition memory impairment was re-instated when the discriminability of the stimuli was made more difficult (black/white pictures of similar objects). The data demonstrate profound functional remodeling within the hippocampus and its interactions with different medial temporal lobe structures from the juvenile period to adulthood, which is substantiated by a parallel morphological maturation of hippocampal intrinsic circuits (Lavenex et al., ; Jabès et al., ).

Sex-dependent role of the amygdala in the development of emotional and neuroendocrine reactivity to threatening stimuli in infant and juvenile rhesus monkeys.

Amygdala dysfunction and abnormal fear and stress reactivity are common features of several developmental neuropsychiatric disorders. Yet, little is known about the exact role the amygdala plays in the development of threat detection and emotional modulation. The current study examined the effects of neonatal amygdala lesions on defensive, emotional, and neuroendocrine reactivity of infant rhesus monkeys reared with their mothers in large species-typical social groups. Monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-A; n = 16) or sham (Neo-C; n = 12) lesions at 24.8 ± 1.2 days of age, or served as behavioral control (Neo-BC; n = 3). Defensive and emotional responses were assessed using the Human Intruder paradigm as infants and as juveniles (2.5 and 12 months of age, respectively), whereas neuroendocrine reactivity was only examined during the juvenile period. As infants, Neo-A animals expressed similar levels of freezing and hostile behaviors as compared to controls, whereas during the juvenile period Neo-A animals expressed significantly less freezing compared to controls. Interestingly, the sex of the infant modulated the behavioral effects of neonatal amygdalectomy, leading to different patterns of behavior depending on the sex and lesion status of the infant. Unlike controls, Neo-A infants did not modulate their behavioral responses based on the salience of the threat. The impact of neonatal amygdalectomy increased with age, such that Neo-A juveniles exhibited fewer emotional behaviors and increased cortisol response to the stressor as compared to controls. These data indicate that the amygdala plays a critical role in the development of both emotional and neuroendocrine reactivity as well as the expression of sexually dimorphic emotional expression.

Development of memory for spatial locations and object/place associations in infant rhesus macaques with and without neonatal hippocampal lesions.

This study traces the development of spatial memory abilities in monkeys and reports the effects of selective neonatal hippocampal lesions on performance across development. Two different versions of the visual paired-comparison (VPC) task were used. The VPC-Spatial-Location task tested memory for object-locations that could be solved using an egocentric spatial frame of reference and the VPC-Object-In-Place task taxed memory for spatial relations using an allocentric reference frame. Eleven rhesus macaques (6 neonatal sham-operated controls and 5 with neonatal neurotoxic hippocampal lesions) were tested on both tasks as infants (8 months), juveniles (18 months), and adults (5-6 years). Memory for spatial locations was present by 18 months of age, whereas memory for object-place relations was present only in adulthood. Also, neonatal hippocampal lesions delayed the emergence of memory for spatial locations and abolished memory for object-place associations, particularly in animals that had sustained extensive and bilateral hippocampal lesions. The differential developmental time course of spatial memory functions and of the effects of neonatal hippocampal lesions on these functions are discussed in relation to morphological maturation of the medial temporal lobe structures in monkeys. Implications of the findings for the neural basis of spatial memory development in humans are also considered.

Acoustic startle and prepulse inhibition deficits in adult monkeys with neonatal lesions of the hippocampus, amygdala and orbital frontal cortex.

Sensory-motor gating, the process of filtering sensory stimuli to modulate motor responses, is impaired in many psychiatric diseases but especially schizophrenia. Sensory-motor gating assessed with the prepulse inhibition paradigm (PPI) measures startle in response to preceding acoustic stimuli. PPI studies in rodents have consistently found that neonatal hippocampal lesions impair sensory-motor gating in adult animals, but its applicability to primates has yet to be tested. The study examined acoustic startle responses and PPI in adult rhesus monkeys with neonatal lesions of the hippocampus (Neo-Hibo), amygdala (Neo-Aibo), and orbital frontal cortex areas 11 and 13 (Neo-Oasp) and with sham-operations (Neo-C). All monkeys were initially habituated to the startle apparatus and assayed for acoustic startle response curves. Subsequently, PPI was measured with the prepulse occurring at 60, 120, 240, 480, 1000 and 5000 msec prior to the pulse onset. No significant group differences in baseline startle were found. Compared to Neo-C monkeys, Neo-Hibo monkeys showed normal startle curves as well as normal PPI at short prepulse delays but prepulse facilitation (PPF) at longer prepulse intervals. Neo-Aibo monkeys displayed enhanced startle responses with only minor changes in PPI, whereas Neo-Oasp monkeys had severe dampening of startle responses and impaired PPI at shorter prepulse intervals. These results support prior evidence from rodent literature of the involvement of each of these areas in the development of the complex cortico-limbic circuit modulating sensory-motor gating and may shade light on the specific neural structures associated with deficits in PPI reported in neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, and post-traumatic disorders.