Superior Neuronal Detection of Snakes and Conspecific Faces in the Macaque Medial Prefrontal Cortex.

Snakes and conspecific faces are quickly and efficiently detected in primates. Because the medial prefrontal cortex (mPFC) has been implicated in attentional allocation to biologically relevant stimuli, we hypothesized that it might also be highly responsive to snakes and conspecific faces. In this study, neuronal responses in the monkey mPFC were recorded, while monkeys discriminated 8 categories of visual stimuli. Here, we show that the monkey mPFC neuronal responses to snakes and conspecific faces were unique. First, the ratios of the neurons that responded strongly to snakes and monkey faces were greater than those of the neurons that responded strongly to the other stimuli. Second, mPFC neurons responded stronger and faster to snakes and monkey faces than the other categories of stimuli. Third, neuronal responses to snakes were unaffected by low-pass filtering of the images. Finally, activity patterns of responsive mPFC neurons discriminated snakes from the other stimuli in the second 50 ms period and monkey faces in the third period after stimulus onset. These response features indicate that the mPFC processes fast and coarse visual information of snakes and monkey faces, and support the hypothesis that snakes and social environments have shaped the primate visual system over evolutionary time.

Pulvinar neurons reveal neurobiological evidence of past selection for rapid detection of snakes.

Snakes and their relationships with humans and other primates have attracted broad attention from multiple fields of study, but not, surprisingly, from neuroscience, despite the involvement of the visual system and strong behavioral and physiological evidence that humans and other primates can detect snakes faster than innocuous objects. Here, we report the existence of neurons in the primate medial and dorsolateral pulvinar that respond selectively to visual images of snakes. Compared with three other categories of stimuli (monkey faces, monkey hands, and geometrical shapes), snakes elicited the strongest, fastest responses, and the responses were not reduced by low spatial filtering. These findings integrate neuroscience with evolutionary biology, anthropology, psychology, herpetology, and primatology by identifying a neurobiological basis for primates' heightened visual sensitivity to snakes, and adding a crucial component to the growing evolutionary perspective that snakes have long shaped our primate lineage.

Habit learning and memory in mammals: behavioral and neural characteristics.

Goal-direct behavior and habit learning represent two forms of instrumental learning; whereas the former is rapidly acquired and regulated by its outcome, the latter is reflexive, elicited by antecedent stimuli rather than their consequences. Habit learning can be generally defined as the acquisition of associations between stimuli and responses. Habits are acquired via experience-dependent plasticity, occurring repeatedly over the course of days or years and becoming remarkably fixed. The distinction between habit learning, as a product of a procedural learning brain system, and a declarative learning system for encoding facts and episodes is based on the hypothesis that memory is composed of multiple systems that have distinct neuroanatomy and operating principles. Here we review recent research analyzing the main behavioral and neural characteristics of habit learning. In particular, we focus on the distinction between goal-directed and habitual behavior, and describe the brain areas and neurotransmitters systems involved in habit learning. The emotional modulation of habit learning in rodents and primates is reviewed, and the implications of habit learning in psychopathology are briefly described.

Comparative anatomy of the pelvic vessels in the bearded capuchin (Sapajus libidinosus) and baboons, apes and modern humans.

Cebus/Sapajus has shown high cognitive and manipulatory behaviour as well as intermittent bipedalism. Although the function of the muscles and bones of this genus has been widely investigated, the arterial system that supports these tissues has not been studied in much detail, and a full description of the blood vessels of the pelvis is still missing. Therefore, we studied the vessels of the pelvis of Sapajus libidinosus in terms of their origin, distribution and muscle irrigation and compared them with those of other primates available in the literature. In general, the distribution pattern and origin of arteries in the pelvis of the bearded capuchin are more similar to those of baboons compared to other primates. This similarity may be because both have a tail, a similar body shape and use, preferentially, quadrupedal movement.

Comparative anatomy of the Sapajus sp. (bearded capuchin) hand with comments on tool use in a parallel evolution with the hominid pathway.

Introduction: Bearded capuchins display a wide variety of manipulatory skills and make routine use of tools in both captivity and the wild. The efficient handling of objects in this genus has led several investigators to assume near-human thumb movements, despite a lack of anatomical studies. Methods: Here, we performed an anatomical analysis of muscles and bones in the capuchin hand. Sapajus morphological traits were quantitatively compared with those of humans, chimpanzees, gorillas, and baboons. Results: The comparative analysis indicated that the Sapajus hand is more similar to that of baboons and least similar to that of humans according to the muscles, bones, and three-dimensional data. Furthermore, these findings suggest that bearded capuchins lack true thumb opponency. Regarding manipulatory skills, they display rather primitive hand traits, with limited resources for precision grasping using the opponens pollicis. Discussion: These findings suggest that bearded capuchins' complex use of tools depends more heavily on their high cognitive abilities than on a versatile hand apparatus. These findings offer crucial insights into the evolution of primate cognition.

Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread ß-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Decreased methylation of the NK3 receptor coding gene (TACR3) after cocaine-induced place preference in marmoset monkeys.

Epigenetic processes have been implicated in neuronal plasticity following repeated cocaine application. Here we measured DNA methylation at promoter CpG sites of the dopamine transporter (DAT1) and serotonin transporter (SERT) and neurokinin3-receptor (NK3-R)-receptor (TACR3) coding genes in marmoset monkeys after repeated cocaine injections in a conditioned place preference paradigm. We found a decrease in DNA methylation at a specific CpG site in TACR3, but not DAT1 or SERT. Thus, TACR3 is a locus for DNA methylation changes in response to repeated cocaine administration and its establishment as a reinforcer, in support of other evidence implicating the NK3-R in reinforcement- and addiction-related processes.

COMFORT behaviour scale and skin conductance activity: what are they really measuring?

AIM: To assess how efficiently the COMFORT behaviour scale measures acute pain in neonates, in comparison with skin conductance activity, a validated measure of pain and stress. METHODS: Images of 36 newborns were analysed before, during and after painful heel pricks to measure glucose levels and compared with skin conductance activity variables. RESULTS: Scale indicators and skin conductance variables were sensitive to changes in the periods 'during-before' and 'during-after' (Wilcoxon's test, p < 0.01). Significant values were found between all scale indicators and number of waves for Kendall's coefficient (p < 0.05), although responses differed when it came to how long they took to increase and correlations varied from fair to moderate (r < 0.6). Facial tension was more closely related to 15 sec after the painful event, while crying and calmness were more closely related to the later intervals (30 and 180 sec). CONCLUSION: All scale indicators were related to skin conductance activity in all periods, indicating pain perception. Facial tension was the most efficient indicator, while others varied in performance after painful events and possibly indicated stress after trauma. These results are discussed from a phenomenological approach and in an anxiety paradigm.

The study of rs324420 (C385A) polymorphism of the FAAH gene of the endocannabinoid system in patients with epilepsy and ADHD.

The endocannabinoid (eCB) system regulates many physiological functions in the central nervous system. Fatty acid amide hydrolase (FAAH) is an essential enzyme in the eCB system, degrading anandamide. Single nucleotide polymorphism (SNP) rs324420 is a common genetic polymorphism of the FAAH gene and has been associated with susceptibility to neurological conditions. This study examined whether the SNP rs324420 (C385A) is associated with epilepsy and attention deficit hyperactivity disorder (ADHD). This study consists of two case-control parts. The first part comprises 250 epilepsy subjects and 250 healthy individuals as controls. The second one comprises 157 cases with ADHD and 136 healthy individuals as controls. Genotyping was carried out using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. Interestingly, the FAAH C384A genotype (OR 1.755, 95 % CI 1.124-2.742, p = 0.013) and allele (OR 1.462, 95 % CI 1.006-2.124, p = 0.046) distribution showed an association with generalized epilepsy. On the other hand, this SNP was not associated with the risk of ADHD. To our knowledge, there was no study on the association between rs324420 (C385A) polymorphism and the risks of ADHD or epilepsy. This study provided the first evidence of an association between generalized epilepsy and rs324420 (C385A) of FAAH. Larger sample sizes and functional studies are warranted to explore the clinical utility of FAAH genotyping as a possible marker for increased generalized epilepsy risk.

Bearded capuchin monkey as a model for Alzheimer's disease research.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using non-human primates in studies, they can bridge mouse models and humans, as non-human primates are phylogenetically close to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed three capuchin brains using structural 7T MRI and neuropathological evaluation. Alzheimer-type pathology was found in one case. Widespread ß-amyloid pathology mainly in the form of focal deposits with variable morphology and high density of mature plaques. Noteworthy, plaque-associated dystrophic neurites, associated with disrupted of axonal transport and early cytoskeletal alteration, were frequently found. Unlike other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Besides, astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. Aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Estrogen, cognitive functions and emotion: an overview on humans, non-human primates and rodents in reproductive years.

Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions,including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines,serotonin and GABA in rodents, primates and humans. Another reason may lie in the wide spread presence of the two classes (a and~) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section,focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle.

A role for the superior colliculus in the modulation of threat responsiveness in primates: toward the ontogenesis of the social brain.

Defense and social mechanisms in primates seem to share, at least in infancy, common neural substrata.Among these, recent research has implicated the primate superior colliculus (SC) on tasks involving visual detection and recognition of threatening stimuli, such as snakes and faces with emotional expressions. There is also evidence that both kinds of stimuli share specific characteristics and command special attention in the primate visual system. The present review focuses on the role of the SC in these seemingly overlapping functions.We present social behavioral data from capuchin monkeys in which the bilateral lesion of the SC induced a transitory impairment of social behaviors. The findings presented here are compared with previous studies, our own and others, on social behaviors and threat detection. We argue that, although the SC may participate in both systems,its role is more prominent in the detection/recognition of threat. Social interactions more likely depend on larger and more complex neural systems, where the SC may play a key role in early infancy. The implications of these recent findings are discussed under an evolutionary perspective.

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms.

Effective connectivity within the corticothalamic circuit in the neuromyelitis optica patients: A comparative study using resting-state fMRI.

Neuromyelitis Optica, which is known as NMO, is a demyelination syndrome and inflammatory condition of the central nervous system that affects the optic nerves. Since structural imaging approaches cannot adequately describe the brain disorders in patients with NMO, functional magnetic resonance imaging (fMRI) can be used. Resting-state fMRI was performed on 25 healthy subjects and 26 NMO patients. After preprocessing the data, the time series belonging to the regions of the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), precuneus (PRE), thalamus (THA), and middle temporal gyrus (MTG) were extracted as components of the corticothalamic circuit. The obtained time series were statistically analyzed as the input of dynamic causal modeling (DCM) in order to evaluate the effective connectivity within the corticothalamic circuit. The statistical analyses showed that the mean of effective connectivity power was significantly higher in the healthy subjects than in the NMO patients. For the healthy subjects, there was no significant difference in effective connectivity power between the two groups of males and females at the significance level of 0.05. In the NMO patients, there was a significant difference between the effective connectivity levels of the male and female groups only for IFG â†’ MFG, in which it was greater in males than in females. The results of our studies showed that resting-state fMRI could exhibit the difference between healthy and NMO subjects.

Plasma nitrate levels and flow-mediated vasodilation in untreated major depression.

OBJECTIVE: Findings from several studies have revealed that major depression is associated with an increased cardiovascular risk. The physiopathologic mechanisms of this association remain unclear, although recently, it has been hypothesized that a decreased production of nitric oxide could be a potential contributor to vascular dysfunction in depressive patients. The objective of this study was to evaluate nitric oxide production and vascular endothelial function in treatment-naive young healthy adults with a first episode of major depression. METHODS: A case-control study in 50 treatment-naive young adults with a first episode of major depression and 50 healthy control subjects was conducted. Plasma levels of nitric oxide metabolites (nitrates/nitrites) were determined using a colorimetric assay based on Griess reaction. Endothelial function was assessed by flow-mediated vasodilation measurements after reactive hyperemia. RESULTS: The mean age of the depressed patients was 22.6 (standard deviation [SD], 4.6) years, whereas the controls were 23.4 (SD, 4.8) years. Sixteen men (32%) and 34 women (68%) were included in each group. The plasma nitrite/nitrate concentrations were significantly lower in depressive subjects compared with healthy controls (17.5 [SD, 4.9] µmol/L versus 21.6 [SD, 7.0] µmol/L, p < .001); however, flow-mediated vasodilation values were similar in both groups (13.1% [SD, 4.3%] versus 12.1% [SD, 5.0%], p = .10). CONCLUSIONS: Decreased plasma concentrations of nitric oxide metabolites are not associated with vascular endothelial dysfunction in young subjects with a first episode of major depression. Reduced nitrate/nitrite levels could reflect a decreased nitric oxide production in the central nervous system of depressed subjects. Further studies are needed to confirm this hypothesis.

Cannabidiol attenuated the maintenance and reinstatement of extinguished methylphenidate-induced conditioned place preference in rats.

Methylphenidate (MPH) is a mild CNS stimulant that has been used in hyperactive children, and patients with neurodegenerative and major depressive disorders. Exposure to MPH-associated cues enhances craving and arousal in drug users. On the other hand, cannabidiol (CBD) has antipsychotic potential that might be useful in alleviating symptoms of drug addiction. The aim of this study was to investigate the effect of CBD administration on extinction and reinstatement of MPH-induced conditioning place preference (CPP) in rats. Male rats received MPH (1, 2.5 or 5 mg/kg, i.p) or morphine (5 or 10 mg/kg, s.c.) during the conditioning phase. Following the establishment of CPP, during extinction training, 60 min prior to every CPP session, animals were given daily ICV CBD (10 or 50 µg/5 µL), vehicle alone (DMSO) 10 % or were treatment-naïve. On the reinstatement day animals after receiving the initial dose of MPH, 0.5 mg/kg, and were placed into the CPP box to evaluate the CPP scoring for 10-min. Our findings indicated that morphine (5 and 10 mg/kg; s.c.) and MPH (1 and 2.5 mg/kg; i.p.) induced a CPP. The ICV administration of both doses of CBD (10 and 50 µg/5 µL) prevented the reinstatement of MPH-induced CPP, which displayed shorter extinction latency compared to treatment-naïve or DMSO 10 % groups. Therefore, CBD's site of action is a potential target for reducing the risk of MPH relapse; however, more investigation is required.

Preferential Neuronal Responses to Snakes in the Monkey Medial Prefrontal Cortex Support an Evolutionary Origin for Ophidiophobia.

Ophidiophobia (snake phobia) is one of the most common specific phobias. It has been proposed that specific phobia may have an evolutionary origin, and that attentional bias to specific items may promote the onset of phobia. Noninvasive imaging studies of patients with specific phobia reported that the medial prefrontal cortex (mPFC), especially the rostral part of the anterior cingulate cortex (rACC), and amygdala are activated during the presentation of phobogenic stimuli. We propose that the mPFC-amygdala circuit may be involved in the pathogenesis of phobia. The mPFC receives inputs from the phylogenically old subcortical visual pathway including the superior colliculus, pulvinar, and amygdala, while mPFC neurons are highly sensitive to snakes that are the first modern predator of primates, and discriminate snakes with striking postures from those with non-striking postures. Furthermore, the mPFC has been implicated in the attentional allocation and promotes amygdala-dependent aversive conditioning. These findings suggest that the rACC focuses attention on snakes, and promotes aversive conditioning to snakes, which may lead to anxiety and ophidiophobia.

Corticosterone impairs contextual fear recall after reactivation in the ovariectomized rat model of menopause.

Menopause affects most physiological processes, including cognitive functions, although, the extent to which these functions are affected is not clear. The aim of this study was to investigate the effect of corticosterone (CORT) administration after reactivation on contextual fear recall in ovariectomized female rats. Adult female rats were ovariectomized and trained in a fear conditioning chamber (conditioned stimulus, CS) using electrical foot shock (unconditioned stimulus, US); with moderate or strong intensities. After reactivation 48 h later, rats were injected with CORT (0.3, 3 or 10 mg/kg) or vehicle. 2, 4 and 11 days after memory reactivation freezing behavior was scored. The results showed that CORT at the low dose of 0.3 mg/kg when injected after memory reactivation impaired memory recall in both moderate and strong shock on the third test (day 11). Because extinction process occurs after repeated presentation of CS without US (electrical shock during reactivation and recall days), memory impairment in our experiments is more likely to be due to increased memory extinction. Our findings suggest that CORT administration after reactivation of fear memory impairs recall in the rat model of menopause and more research is needed to find the exact mechanisms involved in this process which is of great value for treating cognitive problems during menopause.

Cognitive impairment in Parkinson's disease: A clinical and pathophysiological overview.

Cognitive dysfunction in Parkinson's disease (PD) has received increasing attention, and, together with other non-motor symptoms, exert a significant functional impact in the daily lives of patients. This article aims to compile and briefly summarize selected published data about clinical features, cognitive evaluation, biomarkers, and pathophysiology of PD-related dementia (PDD). The literature search included articles indexed in the MEDLINE/PubMed database, published in English, over the last two decades. Despite significant progress on clinical criteria and cohort studies for PD-mild cognitive impairment (PD-MCI) and PDD, there are still knowledge gaps about its exact molecular and pathological basis. Here we overview the scientific literature on the role of functional circuits, neurotransmitter systems (monoaminergic and cholinergic), basal forebrain, and brainstem nuclei dysfunction in PD-MCI. Correlations between neuroimaging and cerebrospinal fluid (CSF) biomarkers, clinical outcomes, and pathological results are described to aid in uncovering the neurodegeneration pattern in PD-MCI and PDD.