This study examined the role of male pubertal maturation on physical growth and development of neurocircuits that regulate stress, emotional and cognitive control using a translational nonhuman primate model. We collected longitudinal data from male macaques between pre- and peri-puberty, including measures of physical growth, pubertal maturation (testicular volume, blood testosterone -T- concentrations) and brain structural and resting-state functional MRI scans to examine developmental changes in amygdala (AMY), hippocampus (HIPPO), prefrontal cortex (PFC), as well as functional connectivity (FC) between those regions. Physical growth and pubertal measures increased from pre- to peri-puberty. The indexes of pubertal maturation -testicular size and T- were correlated at peri-puberty, but not at pre-puberty (23 months). Our findings also showed ICV, AMY, HIPPO and total PFC volumetric growth, but with region-specific changes in PFC. Surprisingly, FC in these neural circuits only showed developmental changes from pre- to peri-puberty for HIPPO-orbitofrontal FC. Finally, testicular size was a better predictor of brain structural maturation than T levels -suggesting gonadal hormones-independent mechanisms-, whereas T was a strong predictor of functional connectivity development. We expect that these neural circuits will show more drastic pubertal-dependent maturation, including stronger associations with pubertal measures later, during and after male puberty.

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.

The lateral prefrontal cortex is known for its contribution to working memory (WM) processes in both humans and animals. Yet, recent studies indicate that the prefrontal cortex is part of a broader network of interconnected brain areas involved in WM. Within the medial temporal lobe (MTL) structures, the perirhinal cortex, which has extensive direct interactions with the lateral and orbital prefrontal cortex, is required to form active/flexible representations of familiar objects. However, its participation in WM processes has not be fully explored. The goal of this study was to assess the effects of neonatal perirhinal lesions on maintenance and monitoring WM processes. As adults, animals with neonatal perirhinal lesions and their matched controls were tested in three object-based (non-spatial) WM tasks that tapped different WM processing domains, e.g., maintenance only (Session-unique Delayed-nonmatching-to Sample, SU-DNMS), and maintenance and monitoring (Object-Self-Order, OBJ-SO; Serial Order Memory Task, SOMT). Neonatal perirhinal lesions transiently impaired the acquisition of SU-DNMS at a short (5 s) delay, but not when re-tested with a longer delay (30 s). The same neonatal lesions severely impacted acquisition of OBJ-SO task, and the impairment was characterized by a sharp increase in perseverative errors. By contrast, neonatal perirhinal lesion spared the ability to monitor the temporal order of items in WM as measured by the SOMT. Contrary to the SU-DNMS and OBJ-SO, which re-use the same stimuli across trials and thus produce proactive interference, the SOMT uses novel objects on each trial and is devoid of interference. Therefore, the impairment of monkeys with neonatal perirhinal lesions on SU-DNMS and OBJ-SO tasks is likely to be caused by an inability to solve working memory tasks with high proactive interference. The sparing of performance on the SOMT demonstrates that neonatal perirhinal lesions do not alter working memory processes per se but rather impact processes modulating impulse control and/or behavioral flexibility.

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.

An earlier study in monkeys indicated that lesions to the mid-portion of the ventral orbitofrontal cortex (OFC), including Walker’s areas 11 and 13 (OFC11/13), altered the spontaneous scanning of still pictures of primate faces (neutral and emotional) and the modulation of arousal. Yet, these conclusions were limited by several shortcomings, including the lesion approach, use of static rather than dynamic stimuli, and manual data analyses. To confirm and extend these earlier findings, we compared attention and arousal to social and nonsocial scenes in three groups of rhesus macaques with restricted lesions to one of three OFC areas (OFC12, OFC13, or OFC14) and a sham-operated control group using eye-tracking to capture scanning patterns, focal attention and pupil size. Animals with damage to the lateral OFC areas (OFC12 and OFC13) showed decreased attention specifically to the eyes of negative (threatening) social stimuli and increased arousal (increased pupil diameter) to positive social scenes. In contrast, animals with damage to the ventromedial OFC area (OFC14) displayed no differences in attention or arousal in the presence of social stimuli compared to controls. These findings support the notion that areas of the lateral OFC are critical for directing attention and modulating arousal to emotional social cues. Together with the existence of face-selective neurons in these lateral OFC areas, the data suggest that the lateral OFC may set the stage for multidimensional information processing related to faces and emotion and may be involved in social judgments.

The medial temporal lobe (MTL) is a collection of brain regions best known for their role in perception, memory, and emotional behavior. Within the MTL, the perirhinal cortex (PRh) plays a critical role in perceptual representation and recognition memory, although its contribution to emotional regulation is still debated. Here, rhesus monkeys with neonatal perirhinal lesions (Neo-PRh) and controls (Neo-C) were tested on the Human Intruder (HI) task at 2 months, 4.5 months, and 5 years of age to assess the role of the PRh in the development of emotional behaviors. The HI task presents a tiered social threat to which typically developing animals modulate their emotional responses according to the level of threat. Unlike animals with neonatal amygdala or hippocampal lesions, Neo-PRh animals were not broadly hyper- or hyporesponsive to the threat presented by the HI task as compared with controls. Instead, Neo-PRh animals displayed an impaired ability to modulate their freezing and anxiety-like behavioral responses according to the varying levels of threat. Impaired transmission of perceptual representation generated by the PRh to the amygdala and hippocampus may explain the animals' inability to appropriately assess and react to complex social stimuli. Neo-PRh animals also displayed fewer hostile behaviors in infancy and more coo vocalizations in adulthood. Neither stress-reactive nor basal cortisol levels were affected by the Neo-PRh lesions. Overall, these results suggest that the PRh is indirectly involved in the expression of emotional behavior and that effects of Neo-PRh lesions are dissociable from neonatal lesions to other temporal lobe structures.

The present study tested whether relational memory processes, as measured by the transverse patterning problem, are late-developing in nonhuman primates as they are in humans. Eighteen macaques ranging from 3–36 months of age, were trained to solve a set of visual discriminations that formed the transverse patterning problem. Subjects were trained at 3, 4–6, 12, 15–24 or 36 months of age to solve three discriminations as follows: 1) A+ vs. B-; 2) B+ vs. C-; 3) C+ vs. A. When trained concurrently, subject must adopt a relational strategy to perform accurately on all three problems. All 36 month old monkeys reached the criterion of 90% correct, but only one 24-month-old and one 15-month-old did, initially. Three-month-old infants performed at chance on all problems. Six and 12-month-olds performed at 75–80% correct but used a ‘linear’ or elemental solution (e.g. A>B>C), which only yields correct performance on two problems. Retraining the younger subjects at 12, 24 or 36 months yielded a quantitative improvement on speed of learning, and a qualitative improvement in 24–36 month old monkeys for learning strategy. The results suggest that nonspatial relational memory develops late in macaques (as in humans), maturing between 15 and 24 months of age.

Transgenic Huntington's disease monkey (HD monkey) model provides great opportunity for studying disease progression that could lead to new insight for developing biomarker, early intervention and novel therapeutics. Whole brain white matter integrity of HD-monkeys was examined longitudinally from 6 to 48 months using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Progressive developmental white matter alterations in HD monkeys were widespread and were observed not only in fiber bundles connecting cortical areas to the striatum (e.g. striatal bundle and external capsule), but also in long association fiber pathways, commissural fibers, and subcortical fiber bundle. In all fiber tracts, the data indicate an arrest in white matter development around 23 months followed by slight decline until adulthood in HD monkeys. The microstructural changes parallel the progressive motor, memory and cognitive decline previously reported as HD monkeys aged. The findings revealed the widespread progressive temporal-spatial microstructural changes in HD monkey brains from infancy to adulthood, suggesting differentiated degenerations across different brain areas during brain development.

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.

This study examined whether selective neonatal hippocampal lesions in monkeys (Macaca mulatta), which left the surrounding cortical areas (parahippocampal cortex) intact, affect contextual learning and memory compared with controls. Monkeys were tested with an automated touch-screen apparatus so that stimuli and contextual cues could be manipulated independently of one another. The data suggest that animals with neonatal hippocampal lesions have sparing of function with regard to contextual learning and memory when (a) contextual information is irrelevant or (b) relevant for good discrimination performance, and (c) when transferring a contextual rule to new discriminations. These findings are at odds with studies examining contextual learning and memory in monkeys with selective adult-onset hippocampal lesions, and those with nonselective neonatal hippocampal lesions, which have demonstrated impairment in contextual learning and memory. Therefore, the sparing of function seen in this study may be attributable to the early nature of the damage and the plastic nature of the infant brain, as well as the intact medial temporal lobe cortical areas as a result of the lesion methodology. Specifically, by removing the hippocampus early in life, before it has begun to function, the parahippocampal (TH/TF) and perirhinal cortices and its interactions with the lateral prefrontal cortex may be able to support context processing throughout life.