Differential effects of post-weaning juvenile stress on the behaviour of C57BL/6 mice in adolescence and adulthood

Rationale: There is evidence that events early in post-weaning life influence brain development and subsequent adult behaviour and therefore play an important role in the causation of certain psychiatric disorders in later life. Exposing rodents to stressors during the juvenile period has been suggested as a model of induced predisposition for these disorders. Objective: This is the first study to examine behavioural and pharmacological changes in adolescence and adulthood following juvenile stress in mice. Materials and methods: Two cohorts of mice were simultaneously exposed to a stress protocol during postnatal days (PND) 25-30. Behavioural assessments reflecting emotional functions, cognitive functions, and psychostimulant sensitivity were then carried out at two time points: one cohort was tested during adolescence (PND 39-54; adolescent group), and the second cohort was tested during adulthood (PND 81-138; adult group). Results: In the adolescent mice, juvenile stress significantly attenuated conditioned freezing and led to decreased anxiety-like behaviour in the elevated plus maze, whereas no effect was observed on these tests in the adult mice. In contrast, adult mice exhibited poor avoidance learning following juvenile stress. When tested during adulthood, the mice stressed during the juvenile period showed a sensitised response to amphetamine compared to controls, whereas the response during adolescence was similar in stressed and control animals. Conclusions: Our results suggest that exposure to stressors during the juvenile period can exert long-term effects on the brain and behaviour and that these effects differ depending on whether the animals are tested during adolescence or adulthoo

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact

Rationale: Schizophrenia has been associated with dysregulation of dopamine (DA) transmission and impairment in a number of experimental tasks, including sensorimotor gating assessed using prepulse inhibition (PPI) and selective attention assessed using latent inhibition (LI). We have demonstrated in previous studies that after withdrawal from escalating (ESC) dosages of amphetamine (AMPH), animals exhibited disruption of LI but no alteration of PPI. Moreover, these animals always showed behavioural sensitization to an AMPH challenge. Objective: In this study, we were interested in testing whether a different administration schedule would elicit disruption of both LI and PPI. Methods: Animals were treated with continuous AMPH release (via osmotic mini-pumps at a dosage of 10mg kg−1 day−1 for 7 days) and tested for their performance in L and PPI during withdrawal in a drug free state. Rats received AMPH treatment during the induction phase in their home cages or in the activity chambers. Following withdrawal, the expression of behavioural sensitization to an AMPH challenge was tested in both cases in the activity chambers. Results: Animals pretreated with AMPH from both groups did not exhibit behavioural sensitization. Withdrawal from continuous administration induced LI attenuation with no effect on PPI. Conclusions: These findings are similar to what was previously found with respect to an ESC AMPH regime. The only difference between the schedules was that the ESC AMPH schedule led to behavioural sensitization whereas the continuous AMPH did not. It is suggested that the expression of sensitization may not be a prerequisite for observed LI disruptio

The amphetamine sensitization model of schizophrenia: relevance beyond psychotic symptoms?

Rationale: A sensitized dopamine system may be linked to the genesis of psychotic symptoms in schizophrenia. Following withdrawal from amphetamine exposures, psychotic-like traits have been robustly demonstrated, but the presence of cognitive/mnemonic deficits remains uncertain. Methods: Adult male Lewis and Fischer rats, differing in cognitive performance, were exposed intermittently to escalating doses of amphetamine over 5weeks. This was effective in producing behavioral sensitization to a subsequent amphetamine challenge. Following 27days of drug withdrawal, the animals were assessed in Pavlovian conditioning, object recognition, and spatial working memory. In addition, prepulse inhibition (PPI), spontaneous motor activity, and anxiety-like behavior were measured. Results: Amphetamine pretreatment induced behavioral sensitization in both rat strains similarly. Working memory was enhanced in Fischer but not Lewis rats following withdrawal. Spontaneous novel object preference was enhanced in sensitized Fischer rats, but was impaired in sensitized Lewis rats, thus effectively reversing the strain difference in non-sensitized controls. In contrast, Pavlovian fear conditioning remained unaffected and so were anxiety-like behavior, open field activity, and PPI. Conclusion: The face validity of the amphetamine withdrawal model for cognitive deficits was limited to the object recognition memory impairment observed in sensitized Lewis rats. Yet, the possibility that enhancing dopaminergic neurotransmission may facilitate object recognition and spatial working memory performance was demonstrated in sensitized Fischer rats. Identification of the mechanisms underlying such strain-dependent effects would be instrumental in the further specifications of the construct validity, and therefore the limitations and potential of the amphetamine sensitization model of schizophreni

Baseline prepulse inhibition expression predicts the propensity of developing sensitization to the motor stimulant effects of amphetamine in C57BL/6 mice

Rationale: The startle reflex to a sudden intense acoustic pulse stimulus is attenuated if the pulse is shortly preceded by a weak prepulse stimulus. This represents a form of sensory gating, known as prepulse inhibition (PPI), observable across species. PPI is modulated by dopamine and readily disrupted by acute amphetamine. Prior repeated exposures to amphetamine also disrupt PPI even when the drug is not present during test, suggesting that a sensitized mesolimbic dopamine system—inducible even by a single exposure to amphetamine—might be responsible. However, this causative link has been challenged by inconsistent efficacy between different amphetamine pre-treatment regimes, which all robustly sensitize the behavioral response to amphetamine. Methods: Here, the presence of such a link in reverse was tested by comparing the propensity to develop amphetamine sensitization between high- and low-PPI expressing individuals identified within a homogeneous cohort of C57BL/6 mice. Comparison of dopamine content including its metabolites was performed separately in drug naïve mice by post-mortem HPLC. Results: Behavioral sensitization was substantially stronger in the low-PPI group compared with the high-PPI group, while the magnitude of their response to the first amphetamine challenge was similar. Dopamine content within the nucleus accumbens and medial prefrontal cortex was significantly higher in low-PPI relative to high-PPI mice. Conclusion: Individuals with weak sensory gating characterized by low basal PPI expression may be more susceptible to the development of dopamine sensitization and therefore at greater risk of developing schizophrenia. Conversely, high baseline expression might predict a resistance to dopaminergic sensitizatio

Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition.

Maternal overnutrition has been associated with increased susceptibility to develop obesity and neurological disorders later in life. Most epidemiological as well as experimental studies have focused on the metabolic consequences across generations following an early developmental nutritional insult. Recently, it has been shown that maternal high-fat diet (HFD) affects third-generation female body mass via the paternal lineage. We showed here that the offspring born to HFD ancestors displayed addictive-like behaviors as well as obesity and insulin resistance up to the third generation in the absence of any further exposure to HFD. These findings, implicate that the male germ line is a major player in transferring phenotypic traits. These behavioral and physiological alterations were paralleled by reduced striatal dopamine levels and increased dopamine 2 receptor density. Interestingly, by the third generation a clear gender segregation emerged, where females showed addictive-like behaviors while male HFD offspring showed an obesogenic phenotype. However, methylome profiling of F1 and F2 sperm revealed no significant difference between the offspring groups, suggesting that the sperm methylome might not be the major carrier for the transmission of the phenotypes observed in our mouse model. Together, our study for the first time demonstrates that maternal HFD insult causes sustained alterations of the mesolimbic dopaminergic system suggestive of a predisposition to develop obesity and addictive-like behaviors across multiple generations

Pre- and postnatal high fat feeding differentially affects the structure and integrity of the neurovascular unit of 16-month old male and female mice

Compelling experimental and clinical evidence supports a role for maternal obesity in offspring health. Adult children of obese mothers are at greater risk of obesity, diabetes, coronary heart disease and stroke. These offspring may also be at greater risk of age-related neurodegenerative diseases for which mid-life obesity is a risk factor. Rodent diet-induced obesity models have shown that high fat (HF) diet consumption damages the integrity of the blood-brain barrier (BBB) in the adult brain. However, there is currently little information about the effect of chronic HF feeding on the BBB of aged animals. Moreover, the long-term consequences of maternal obesity on the cerebrovasculature of aged offspring are not known. This study determined the impact of pre- and postnatal HF diet on the structure and integrity of cerebral blood vessels in aged male and female mice. Female C57Bl/6 mice were fed either a 10% fat control (C) or 45% HF diet before mating and during gestation and lactation. At weaning, male and female offspring were fed the C or HF diet until sacrifice at 16-months of age. Both dams and offspring fed the HF diet weighed significantly more than mice fed the C diet. Postnatal HF diet exposure increased hippocampal BBB leakiness in female offspring, in association with loss of astrocyte endfoot coverage of arteries. Markers of tight junctions, pericytes or smooth muscle cells were not altered by pre- or postnatal HF diet. Male offspring born to HF-fed mothers showed decreased parenchymal GFAP expression compared to offspring of mothers fed C diet, while microglial and macrophage markers were higher in the same female diet group. In addition, female offspring exposed to the HF diet for their entire lifespan showed more significant changes in vessel structure, BBB permeability and inflammation compared to male animals. These results suggest that the long-term impact of prenatal HF diet on the integrity of cerebral blood vessels differs between male and female offspring depending on the postnatal diet. This may have implications for the prevention and management of age- and obesity-related cerebrovascular diseases that differentially affect men and women

Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition

We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, i.e. deficient GABA transmission, within prefrontal cortex and hippocampus for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline. Regional neural disinhibition, disrupting spatio-temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically-relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function); moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus, but requires prefrontal-striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support that prefrontal and hippocampal neural disinhibition contributes to clinically relevant cognitive deficits, and we consider pharmacological strategies for ameliorating cognitive deficits by rebalancing disinhibition-induced aberrant neural activity

Juvenile stress enhances anxiety and alters corticosteroid receptor expression in adulthood

Background Exposure to stress in early life is correlated with the development of anxiety disorders in adulthood. The underlying mechanisms are not fully understood, but an imbalance in corticosteroid receptor (CR) expression in the limbic system, particularly the hippocampus, has been implicated in the etiology of anxiety disorders. However, little is known about how prepubertal stress in the so called “juvenile” period might alter the expression of these receptors. Aims Therefore, the aim of this study was to investigate how stress experienced in the juvenile phase of life altered hippocampal expression of CRs and anxiety behaviors in adulthood. Materials and methods We used a rodent model to assess the effects of juvenile stress on hippocampal CR expression, and performance in three behavioral tests of anxiety in adulthood. Results Juvenile stress (JS) increased anxiety‐like behavior on the elevated plus maze, increased mineralocorticoid receptor (MR) expression, and decreased the ratio of glucocorticoid receptor (GR) to MR expression in the hippocampus of adult animals. Females demonstrated lower levels of anxiety‐type behavior and increased activity in three behavioral tests, and had greater expression of GR and GR:MR ratio than males, regardless of treatment. Discussion and conclusion These results demonstrate that JS can alter the expression and balance of CRs, providing a potential mechanism for the corresponding increase in anxiety behavior observed in adulthood. Further evidence for the role of CR expression in anxiety is provided by sex differences in anxiety behavior and corresponding alterations in CR expression