Chronic MK-801 administration provokes persistent deficits in social memory in the prairie vole (Microtus ochrogaster): A potential animal model for social deficits of schizophrenia.

The prairie vole (Microtus ochrogaster) is a rodent species that has been used extensively to study biological aspects of human social bonding. Nevertheless, this species has not been studied in the context of modeling social deficits characteristic of schizophrenia. Building on studies in rodents that show that sub-chronic administration of an NMDA receptor antagonist induces persistent behavioral and neurological characteristics of schizophrenia, we administered MK-801 (0.2 mg/kg, daily, for 7 days) or physiological saline to young adult (45 days old) virgin male voles. At 69 days of age, we paired these males with virgin females. 24 h later, we assessed the males' social investigation of each female across the first 5 min of a three-hour preference test, and side-by-side contact with each female during the last hour of the test. Unlike saline-treated males, MK-801-treated males did not preferentially investigate the unfamiliar female, indicating a deficit in social memory. Although males of both groups preferentially spent time with their female partner, regression analysis revealed that deficits in social memory predicted lower partner preference in MK-801-treated males. We interpret these results in the context of recent studies of the natural history of the prairie vole as well as in the context of cognitive deficits in schizophrenia and propose that the social component of episodic memory might influence an individual's capacity to form and maintain long-term social bonds.

Effects of intrauterine position during gestation on specific endocrine and behavioral parameters that impact reproduction in domestic rabbits.

Prior studies from others, performed in a different breed, reported that doe rabbits developing between two male siblings (2 M) during gestation display characteristics indicative of masculinization: larger anogenital distance (AGD), larger submandibular glands, and higher chinning frequency than females with zero (0 M) or one (1 M) contiguous brothers. Similar effects are provoked by injecting androgens to the pregnant doe suggesting that prenatal androgen exposure masculinizes female embryos. To further understand the scope of such masculinization we compared 0 M, 1 M, and 2 M females regarding behavioral, neuroendocrine, and somatic parameters, related or not to reproduction. IUP did not impact: body weight, sexual receptivity, mating-induced LH secretion, maternal nest-building, litter size, or milk output. At puberty: a) chinning frequency was: 0 M and males>1 M and 2 M; b) ambulation in open field was lowest in 1 M females and males. IUP effects on AGD were significant only on postnatal day 1: 0 M, 1 M, and males>2 M, in contrast to earlier study. Willingness to nurse at delivery was less frequent in 2 M than in 1 M and 0 M does and correlated with nursing occurrence across lactation. Does that did not nurse at parturition delivered fewer kits/min than those that nursed then, regardless of IUP. The duration of nursing bouts across lactation was significantly longer in the1 M and 2 M does that showed this behavior on postpartum days 1-20. Our findings indicate that IUP is associated with alterations in specific aspects of postpartum maternal behavior.

Multiparity favors same-sex partner preference in male rats.

Same-sex partner preference is present in many mammals, including rodents. Several possible causal factors have been proposed for the establishment of this preference. The Fraternal Birth Order effect refers to the observation that older brothers increase the probability of homosexuality in men, but no experiment has analyzed this possibility. In this study, partner preference (tested in a three compartments box) and female and male sexual behavior (studied in a cylindrical arena) were evaluated in young male rats (3 months) born to multiparous mothers that had 4-6 previous gestations and around 12 months of age. Control groups were young male rats born to primiparous young (4 months) or aged (12 months) mothers. In the partner preference test, the males born to multiparous dams spent less time interacting with the receptive female and more time interacting with the sexually active male, and a 39% exhibited same-sex partner preference. This high percentage seems related to multiparity of their mothers and not to maternal age, because the males born to primiparous aged females (12 months) showed a similar low proportion of same-sex partner preference than the males born to young (4 months) primiparous females (4%). In the sexual behavior tests, no male born of a multiparous dam and with same-sex preference ejaculated and 54% displayed proceptivity and lordosis. Present results suggest that the fraternal birth order effect may occur also in rats.

Mental health needs and accessing specialised healthcare in Mexican children with mental disorders: gender- and diagnosis-dependent differences.

BACKGROUND: Access describes factors that influence the initial contact or use of services, emphasising both the characteristics of patients and the health resources that influence the use of health services. AIMS: To compare Mexican boys and girls with mental disorders, with respect to primary diagnosis, symptom onset, and seeking and accessing specialised mental health services (SMHS). METHOD: Longitudinal data were collected from primary caregiver-reported assessments of 397 child-caretaker dyads (child mean age 12.17 years, range 5-18 years, 63% male) that were obtained in two psychiatric hospitals specialising in child mental healthcare. Student t-tests and χ2-tests were applied to compare boys and girls regarding their diagnosis and variables associated with the seeking of and access to SMHS. RESULTS: Hyperkinetic disorder was the most prevalent diagnosis in boys, whereas depressive disorder and anxiety disorder were most prevalent in girls. The mean age at symptom onset for boys was 7 years, compared with 10 years for girls. Hyperkinetic disorder had the earliest symptom onset (mean 5.9 years), followed by depressive disorder (mean 9.8 years) and anxiety disorder (mean 12 years). Delayed access to SMHS was associated with initially seeking care from a psychologist, whereas quicker access was associated with affiliation with the (now defunct) Popular Insurance, a programme that served low-income and uninsured individuals. CONCLUSIONS: Programmes aimed at children's mental health education and early intervention should consider gender- and diagnosis-related differences in symptom onset and trajectory. Access to SMHS might be improved by rapid identification by parents, educators, primary-care physicians and psychologists.

Analysis of Educational Attainment in a Mexican Psychiatric Patient Population with Bipolar or Psychotic Disorders.

Schizophrenia has been associated with premorbid poor educational performance and low educational attainment (EA). However, some studies have found positive associations between psychotic disorders and excellent scholastic performance. In the present study, we examined the association between EA and several clinical and nonclinical characteristics in psychiatric patients diagnosed with psychotic or bipolar disorders. Data were obtained from the files of 1132 patients who entered a major Mexico City psychiatric hospital during the years 2009-2010 for the treatment of psychotic symptoms and who were subsequently diagnosed with schizophrenia, bipolar, schizoaffective, or another psychotic disorder. Chi-squared tests, t-tests, and Cox regression analysis were applied to explore associations between EA and factors including gender, familial history of mental illness, premorbid personality characteristics, age of symptom onset, diagnosis, civil status, and current employment. Family history of mental illness decreased the hazard of having lower EA (B = -0.137, p = 0.025, ExpB = 0.872, 95% CI = 0.774-0.983), while a schizophrenia diagnosis independently increased it (B = 0.201, p = 0.004, ExpB = 1.223, 95% CI = 1.068-1.401). In male patients (but not in females), family history of mental illness was significantly associated with higher EA, while in female patients, premorbid schizoid-like personality characteristics were associated with lower EA. For both genders, lower EA was associated with having more children and being employed in manual labor, while higher EA was associated with professional employment. Conclusions: Compared with bipolar disorder, a schizophrenia diagnosis is associated with lower EA; however, familial history of mental illness and premorbid schizoid-like characteristics independently favor higher and lower EA in males and females, respectively. Since lower EA is generally associated with a lower economic status, special preventative attention should be given to students at high risk for schizophrenia, particularly those displaying a schizoid-like personality.

Tactile stimulation prevents disruptions in male rat copulatory behavior induced by artificial rearing.

Early life social interactions in gregarious mammals provide an important source of stimulation required for the development of species-typical behaviors. In the present study, complete deprivation of maternal and littermate contact through artificial rearing was used to examine the role of early social stimulation on copulatory behavior and the ejaculate in adult rats. We found that artificially reared naïve male rats were sexually motivated; nevertheless, they did not acquire the level of sexual experience that typically occurs during copulatory training. Disrupted expression of sexual experience of artificially reared rats was demonstrated by an inconsistent pattern of ejaculatory behavior across training tests. Artificial tactile stimulation applied during isolation prevented this disruption and rats achieved ejaculation in most copulatory tests. Despite the irregularity of ejaculatory behavior in isolated rats, their sperm count and seminal plug were similar to control maternally reared (sexually experienced) and artificially-reared rats that received tactile stimulation. These results suggest that tactile sensory information provided by the mother and/or littermates to the offspring is crucial for the development of copulatory behavior. The absence of social and/or tactile stimulation during early life compromises the ability of male rats to gain sexual experience in adulthood.

Rabbit Maternal Behavior: A Perspective from Behavioral Neuroendocrinology, Animal Production, and Psychobiology.

Rabbit maternal behavior (MB) impacts meat and fur production on the farm, survival of the species in the wild, and pet welfare. Specific characteristics of rabbit MB (i.e., three-step nest building process; single, brief, daily nursing bout) have been used as models for exploring particular themes in neuroscience, like obsessive-compulsive actions, circadian rhythms, and cognition. Particular hormonal combinations regulate nest building by acting on brain regions controlling MB in other mammals. Nonhormonal factors like type of lodging and the doe's social rank influence nursing and milk production. The concurrency of pregnancy and lactation, the display of nonselective nursing, and the rapid growth of altricial young - despite a minimal effort of maternal care - have prompted the study of mother-young affiliation, neurodevelopment, and weaning. Neurohormonal mechanisms, common to other mammals, plus additional strategies (perhaps unique to rabbits) allow the efficient, adaptive display of MB in multiple settings.

Pediatric neuropsychiatric syndromes associated with infection and microbiome alterations: clinical findings, possible role of the mucosal epithelium, and strategies for the development of new animal models.

INTRODUCTION: Pediatric obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) have been associated with respiratory tract infections and alterations in the intestinal microbiome, respectively. Pediatric Acute-onset Neuropsychiatric Syndromes (PANS) refers to the sudden onset of neuropsychiatric symptoms that are triggered by several infectious and non-infectious factors. Studies indicate that inflammation plays an important etiological role in PANS, as well as in ASD associated with gut dysbiosis. AREAS COVERED: The present review provides an overview of clinical studies of PANS and ASD associated with gastrointestinal symptoms, as well as existing strategies for investigating these syndromes in rodent models. The authors highlight similarities between these syndromes that may provide clues to common etiological mechanisms. EXPERT OPINION: Although data from animal models are consistent with an important role for anti-neuronal antibodies in PANS triggered by GAS infection, we lack models for identifying pathophysiological mechanisms of PANS associated with other infectious and noninfectious triggers. The authors propose an animal modeling strategy that incorporates known vulnerability and triggering factors for PANS into the modeling process. This novel strategy should expand our understanding of the pathophysiology of PANS, as well as facilitate the development of new pharmacological treatments for PANS and related syndromes.

Family History of Psychiatric Disorders and Clinical Factors Associated With a Schizophrenia Diagnosis.

BACKGROUND: Schizophrenia (SCH) and bipolar disorder (BD) have both shared and unique genetic risk factors and clinical characteristics. The aim of the present study was to identify potential risk factors significantly associated with SCH, relative to a BD reference group. METHODS: Data were obtained from medical records of patients that entered a major Mexico City hospital during 2009-2010 presenting psychotic symptoms (n = 1132; 830 cases of SCH, 302 cases of BD; 714 men and 418 women). SCH and BD diagnoses were compared with respect to a number of family and clinical characteristics. Logistic and linear regression analyses were used to respectively identify factors selectively associated with the SCH diagnosis relative to the BD diagnosis and explore the relationship between PANSS scores and parental age at time of birth to the age of SCH onset. RESULTS: Patients with SCH showed greater functional impairment than those with BD. Family history of mental illness, premorbid schizoid-like personality, and obstetric trauma were significantly associated with the SCH diagnosis. The association of obstetric trauma with SCH was greatest in male patients with a family history of mental illness. In women, increased paternal and decreased maternal age at time of the patient's birth were associated with an earlier age of SCH onset. CONCLUSION: Male gender, showing premorbid schizoid-like personality, familial SCH, and obstetric trauma are risk factors that distinguish SCH from BD. Additionally, our results suggest that risk for SCH relative to BD may be importantly influenced by interactions between familial risk, gender, and obstetric trauma.

Oxytocin induces lordosis behavior in female rats through the prostaglandin E2/GnRH signaling system.

Intracerebroventricular (icv) administration of oxytocin (OT) induces robust lordosis behavior (lordosis quotient and lordosis intensity) in estrogen-primed rats. The present study explored the hypothesis that the OT-Prostaglandin E2-GnRH pathway (a pathway produced in astrocytes) is involved in the facilitation of lordosis behavior by icv infusion of OT (2 µg). In Experiment 1, we tested the involvement of the OT receptor (OTR) by infusion of the OTR antagonist, atosiban (ATO). OT-induced lordosis was significantly reduced at both 30 and 120 min by prior infusion of ATO. In Experiment 2, we studied the effects of aspirin (COX2 inhibitor) and ONO-AE3-208 (ONO; EP4 prostaglandin receptor antagonist) on OT-induced lordosis. Infusions of both compounds diminished OT-induced lordosis at both 120 and 240 min. In Experiment 3, the involvement of the GnRH-1 receptor inhibitor antide on OT-induced lordosis was evaluated. Antide significantly inhibited OT-induced lordosis at all times tested. These data indicate that the OT/PGE2/GnRH pathway is involved in the expression of OT-induced lordosis behavior, an effect that may be occurring directly in hypothalamic astrocytes.

From the Clinic to the Laboratory, and Back Again: Investigations on Cannabinoids and Endocannabinoid System Modulators for Treating Schizophrenia.

The present mini-review focuses on animal models of schizophrenia that have explored the effects of cannabidiol (CBD; a non-psychoactive component of cannabis) or the pharmacological manipulation of the endocannabinoid system on behavioral and cognitive outcome measures. First, results of some relevant clinical studies in this area are summarized, and then pre-clinical work on animal models of schizophrenia based on NMDA receptor antagonism or neurodevelopmental manipulations are discussed. A brief overview is given of the theoretical framework on which these models are based, along with a concise summary of results that have been obtained. Clinical results using CBD for schizophrenia seem promising and its effects in animal models of schizophrenia support its potential as a useful pharmacotherapy. Animal models have been paramount for elucidating the actions of CBD and the function of the endocannabinoid system and for identifying novel pharmacological targets, such as cannabinoid receptors and anandamide. However, more attention needs to be placed on defining and applying independent variables and outcome measures that are comparable between pre-clinical and clinical studies. The objective of this review is, on the one hand, to emphasize the potential of such models to predict clinical response to experimental drugs, and on the other hand, to highlight areas in which research on such models could be improved.

The Impact of Health Policies and Sociodemographic Factors on Doubling Time of the COVID-19 Pandemic in Mexico.

Background. The doubling time is the best indicator of the course of the current COVID-19 pandemic. The aim of the present investigation was to determine the impact of policies and several sociodemographic factors on the COVID-19 doubling time in Mexico. Methods. A retrospective longitudinal study was carried out across March-August, 2020. Policies issued by each of the 32 Mexican states during each week of this period were classified according to the University of Oxford Coronavirus Government Response Tracker (OxCGRT), and the doubling time of COVID-19 cases was calculated. Additionally, variables such as population size and density, poverty and mobility were included. A panel data model was applied to measure the effect of these variables on doubling time. Results. States with larger population sizes issued a larger number of policies. Delay in the issuance of policies was associated with accelerated propagation. The policy index (coefficient 0.60, p < 0.01) and the income per capita (coefficient 3.36, p < 0.01) had a positive effect on doubling time; by contrast, the population density (coefficient -0.012, p < 0.05), the mobility in parks (coefficient -1.10, p < 0.01) and the residential mobility (coefficient -4.14, p < 0.01) had a negative effect. Conclusions. Health policies had an effect on slowing the pandemic's propagation, but population density and mobility played a fundamental role. Therefore, it is necessary to implement policies that consider these variables.

Dataset on c-Fos expression within components of corticostriatal thalamocortical circuits during the expression of a compulsive-like behavior in the female rabbit: Brain-behavior relationships.

The dataset describes regional brain c-Fos expression and a component of maternal nest building behavior ("straw carrying") in 5 late term pregnant rabbits that had been allowed to interact with straw (a nest building material) for a discrete period (30 min), during which repetitive straw carrying behavior was initiated. Animals were sacrificed for brain c-Fos immunoreactivity 1 h after straw was placed into their cage. Regional brain c-Fos expression: Neuronal c-Fos expression is known to associate with a sustained increase in neuronal excitation above resting levels, primarily due to its induction in response to increased glutamatergic input and corresponding activation of the NMDA receptor. In practice, c-Fos expression is taken to be an indication of an increase in "neuronal activity". Importantly, there is a lag of approximately 20 to 30 min between the onset of the stimulus that caused increased excitation, and the initiation of neuronal c-Fos expression, and c-Fos has a cellular half-life of approximately 1 h. Thus, the pattern of brain c-Fos expression within a brain histological section represents a composite snapshot of "superimposed" regional activations that occurred within approximately 30 min to 2 h prior to sacrifice. Behavioral variables: Behavioral variables included in the present dataset are those that reflect the repetitive nature of straw carrying (straw carrying cycle frequency), as well as individual subcomponents of this behavior (collecting straw, interacting with the nest site), and indicators of the "rigidity" of expression of these subcomponents across all cycle repetitions (standard deviations of time spent collecting straw, time spent interacting with nest site). Exploratory Factor Analysis (EFA) with cluster rotation was applied in an exploratory manner in order to clarify correlational relationships between regional c-Fos expression and specific behavioral variables.

The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap.

This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.

Protein kinase inhibitors infused intraventricularly or into the ventromedial hypothalamus block short latency facilitation of lordosis by oestradiol.

An injection of unesterified oestradiol (E2 ) facilitates receptive behaviour in E2 benzoate (EB)-primed, ovariectomised female rats when it is administered i.c.v. or systemically. The present study tested the hypothesis that inhibitors of protein kinase A (PKA), protein kinase G (PKG) or the Src/mitogen-activated protein kinase (MAPK) complex interfere with E2 facilitation of receptive behaviour. In Experiment 1, lordosis induced by i.c.v. infusion of E2 was significantly reduced by i.c.v. administration of Rp-cAMPS, a PKA inhibitor, KT5823, a PKG inhibitor, and PP2 and PD98059, Src and MAPK inhibitors, respectively, between 30 and 240 minutes after infusion. In Experiment 2, we determined whether the ventromedial hypothalamus (VMH) is one of the neural sites at which those intracellular pathways participate in lordosis behaviour induced by E2 . Administration of each of the four protein kinase inhibitors into the VMH blocked facilitation of lordosis induced by infusion of E2 also into the VMH. These data support the hypothesis that activation of several protein kinase pathways is involved in the facilitation of lordosis by E2 in EB-primed rats.

Obsessive compulsive disorder (OCD): Current treatments and a framework for neurotherapeutic research.

We briefly review current approaches to the diagnosis and treatment of OCD, noting their lack of a strong theoretical foundation. In keeping with the Research Domain Criteria project (RDoC) calls for reconceptualizing psychopathology in ways that better link up with normal brain systems, we advance an adaptationist, brain-network perspective on OCD and propose that OCD represents a dysfunction in the stopping dynamics of a normal brain network that evolved to handle potential danger. We then illustrate how this theoretical perspective can be used to organize possibilities for research on neurotherapeutics for OCD and suggest novel directions for future work.

Copulation-induced antinociception in female rats is blocked by atosiban, an oxytocin receptor antagonist.

AIMS: We hypothesized that copulation-induced temporary anti-nociception in female rats is mediated by the activation of central and/or peripheral oxytocin receptors. To test this hypothesis, we assessed the effects of intraperitoneal (ip), intrathecal (it), and intra-cerebroventricular (icv) administration of an oxytocin receptor antagonist (atosiban), on copulation-induced temporary anti-nociception in estrous rats. MAIN METHODS: The treatment groups were ovariectomized rats pre-treated subcutaneously (sc) with 10 µg of estradiol benzoate (EB) followed 24 h later by an sc injection of 5 µg EB, and 4 h later, by an sc injection of 2 mg progesterone (P4). Rats were then administered saline vehicle (ip, it, or icv: control groups) or atosiban (500 µg/kg ip; 500 ng it; or 500 ng icv: experimental groups). Thirty minutes after drug or saline administration, their sexual behavior was tested by pairing with a sexually-experienced male rat. Brief pulse trains of 50 Hz, 300 ms duration, supra-threshold tail electrical shocks (STS) were delivered before and during copulatory activity i.e., while the female was receiving mounts, intromissions, or ejaculations, and we recorded whether vocalization occurred in response to each STS. KEY FINDINGS: Replicating our previous findings, the vocalization response to STS in control rats was significantly attenuated during intromissions and ejaculations, compared to their baseline (pre-mating) response, indicative of anti-nociception. By contrast, rats pre-treated with atosiban (each route of administration) failed to show an attenuation of the vocalization response to shock. SIGNIFICANCE: These findings provide evidence that the temporary anti-nociceptive effect of copulation in female rats is mediated by copulation-induced release of endogenous oxytocin in brain, spinal cord and periphery.