The Effects of Maternal Behavior and Environmental Enrichment on Behavior and Cognition in Sprague-Dawley Rats

Early environments critically impact the development of many organisms. Exposure to varying maternal care behaviors and environmental enrichments can cause persisting changes throughout a rat’s life. The current study examines the effect of high and low levels of maternal care and environmental enrichment on anxiety, resilience, spatial memory, and non-spatial memory. Maternal rats were identified as Good or Bad mothers based on their pup retrieval speed. Their pups were then sorted by maternal care they experienced and placed into two housing conditions: enriched, and control (resulting in four conditions total). Each group was assessed on four behavioral tests including the elevated plus maze to measure anxiety, the novel object preference test and object location memory task to measure non-spatial and spatial memory respectively, and the forced swim test to measure resiliency based on level of escape behavior. Preliminary results found that Good mothers had better spatial and non-spatial memory than Bad mothers. Behavioral results from the adolescent pups showed pups raised by Good mothers who were in enriched housing had better non-spatial memory. Pups that had a Bad mother and lived in control housing exhibited deficits in spatial memory. In addition, the level of maternal care determined the level of resiliency in the adolescent pups. Overall, environmental enrichment and early maternal behavior had an influence on the memory and resiliency in rats

Stress during Adolescence Increases Novelty Seeking and Risk-Taking Behavior in Male and Female Rats

Adolescence is a period of major physical, hormonal, and psychological change. It is also characterized by a significant increase in the incidence of psychopathologies and this increase is gender-specific. Likewise, stress during adolescence is associated with the development of psychiatric disorders later in life. Previously, using a rat model of psychogenic stress (exposure to predator odor followed by placement on an elevated platform) during the pre-pubertal period (postnatal days 28–30), we reported sex-specific effects on auditory and contextual fear conditioning. Here, we study the short-term impact of psychogenic stress before and during puberty (postnatal days 28–42) on behavior (novelty seeking, risk taking, anxiety, and depression) and hypothalamus–pituitary–adrenocortical (HPA) axis activation during late adolescence (postnatal days 45–51). Peri-pubertal stress decreased anxiety-like behavior and increased risk taking and novelty seeking behaviors during late adolescence (measured with the elevated plus maze, open field and exposure to novel object tests and intake of chocopop pellets before or immediate after stress). Finally neither depressive-like behavior (measured at the forced-swim test) nor HPA response to stress (blood corticosterone and glucose) were affected by peri-pubertal stress. Nevertheless, when controlling for the basal anxiety of the mothers, animals exposed to peri-pubertal stress showed a significant decrease in corticosterone levels immediate after an acute stressor. The results from this study suggest that exposure to mild stressors during the peri-pubertal period induces a broad spectrum of behavioral changes in late adolescence, which may exacerbate the independence-building behaviors naturally happening during this transitional period (increase in curiosity, sensation-seeking, and risk-taking behaviors)

Maternal separation with early weaning: a novel mouse model of early life neglect

<p>Abstract</p> <p>Background</p> <p>Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse.</p> <p>Results</p> <p>In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect.</p> <p>Conclusions</p> <p>These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.</p

Effect of Maternal Behavior on Anxiety, Resilience, and Memory in Sprague-Dawley Rats

This study seeks to determine the extent that maternal care of rodents influences anxiety levels, memory, and resiliency in the next generation. After categorizing maternal rats as Good and Bad mothers through a pup recognition test, they and their pups were put through a battery of behavioral tasks to assess anxiety (Elevated Plus Maze), memory (Novel Object Preference Test and Object Location Memory Task), and resiliency (Forced Swim Test). Preliminary results found that Good mothers have superior spatial and non-spatial memory in comparison to the Bad mothers. In addition, the pups raised by Good mothers showed greater resilience in comparison to pups raised by Bad mothers based on escape behaviors seen in the Forced Swim Test. This suggests that the type of mother a rodent is (i.e., Good mother or Bad mother) has on effect on their memory and the type of maternal care received by offspring influences resiliency

Fluid Percussion Injury in the Rat as an Animal Model of Concussion: Cumulative Effects of Repeated Concussion and its Treatment by Anti-CD11d Antibody

Traumatic brain injury is a global health concern with limited treatment options currently available. Concussion is the most common form of traumatic brain injury, and although a single concussion rarely results in long-term neurological dysfunction, repeated concussion can result in cumulative damage and chronic neurodegenerative disease. However, little is known about the factors and mechanisms of concussion involved in these detrimental effects. Animal models provide a means to examine the factors and mechanisms involved in traumatic brain injury, as well as potential treatments, in experiments that cannot be conducted using human participants. In the present thesis a fluid percussion model of traumatic brain injury was used to study single and repeated concussion in adult male Long-Evans rats. Anti-CD11d integrin antibody, a novel compound that reduces neuroinflammation by targeting the infiltration of peripheral leukocytes into the brain after traumatic brain injury, was evaluated as a potential treatment for concussion. In Study 1 a single mild lateral fluid percussion injury (1.0-1.5 atm) caused short-term (24 hrs) behavioral impairments and neuropathological alterations indicative of neuroinflammation and axonal injury. In Study 2, three or five mild lateral fluid percussion injuries given at 5-day intervals caused cumulative short-term (24 hrs) and long-term (8 weeks) behavioral impairments and neuropathological alterations indicative of neuroinflammation and cortical loss. These results appear to validate the use of single and repeated mild lateral fluid percussion injuries to model important aspects of human concussion. In Study 3 anti-CD11d antibody administered after a single moderate lateral fluid percussion injury (2.5 - 3.0 atm) reduced cognitive, emotional, and motor impairments, and also reduced neuroinflammation and neuronal loss relative to injured rats treated with a control antibody. In Study 4 anti-CD11d antibody administered after each of three repeated mild lateral fluid percussion injuries similarly reduced cognitive, emotional, and motor impairments, and neuroinflammation and cortical loss relative to injured rats treated with a control antibody. These novel findings suggest the involvement of infiltrating peripheral leukocytes and neuroinflammation in both single and repeated concussion, and they support the further investigation of anti-CD11d antibody as a potential treatment for concussion

Postweaning Enriched Environment Enhances Cognitive Function and Brain-Derived Neurotrophic Factor Signaling in the Hippocampus in Maternally Separated Rats

Adverse environments during early life may lead to different neurophysiological and behavioral consequences, including depression and learning and memory deficits that persist into adulthood. Previously, we demonstrated that exposure to an enriched environment during adolescence mitigates the cognitive impairment observed after maternal separation in a task-specific manner. However, underlying neural mechanisms are still not fully understood. The current study examines the effects of neonatal maternal separation (MS) and postweaning environmental enrichment (EE) on spatial learning and memory performance in a short version of the Barnes Maze, active and passive behaviors in the forced swim test, and on TrkB/BDNF receptor expression in the hippocampus. Our results revealed that MS impaired acquisition learning and that enriched rats performed better than non-enriched rats in acquisition trials, regardless of early conditions. During the probe, enriched-housed rats demonstrated better performance than those reared in standard conditions. No significant differences between groups were found in the forced swim test. Both MS and EE increase full-length TrkB expression, and the combination of MS and EE treatment caused the highest levels of this protein expression. Similarly, truncated TrkB expression was higher in the MS/EE group. Animal facility rearing (AFR) non-enriched groups present the lowest activation of phosphorylated Erk, a canonical downstream kinase of TrkB signaling. Taken together, our results demonstrate the importance of enriched environment as an intervention to ameliorate the effects of maternal separation on spatial learning and memory. TrkB/BDNF signaling could mediate neuroplastic changes related to learning and memory during exposure to enriched environment.Fil: Cordier, Javier Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Aguggia, Julieta Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Danelon, Víctor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Mir, Franco Rafael. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Rioja; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.exactas Físicas y Naturales. Departamento de Fisiología. Cátedra de Fisiología Animal; ArgentinaFil: Rivarola, María Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.exactas Físicas y Naturales. Departamento de Fisiología. Cátedra de Fisiología Animal; ArgentinaFil: Masco, Daniel Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces “detrimental” effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a “substitute” mother. The maternal care of biological and “substitute” mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the “substitute” mother did not exhibit overt maltreatment. A mixture of “detrimental” and “beneficial” effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may “buffer” the effects of ELS in a context-dependent manner

P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions

Sex Differences in Behavioral Responses to Repeat Subconcussive Events

Although concussions, especially those in athletes and military, have become a popular focus of neurotrauma research, subconcussions occur with higher frequency and are less well-studied. A subconcussion is loosely defined as an impact to the head that does not result in a diagnosable concussion but can result in neuronal alterations. Repeat subconcussions have been shown to produce behavioral impairments along with neuropathology that is similar to or worse than those seen in a single concussion injury. These studies have primarily included male subjects. Given the potential effects of hormones and NIH’s call for sex-inclusion in biomedical research, assessing female responses to injury is essential. The current study was designed to model repeat subconcussions in the adult rat and examine sex differences in behavioral responses to injury. Using a model of closed head injury previously created in our lab, this study modified the intensity of the impact to create a subconcussive impact. All rats received a single concussion, single subconcussion, repeat subconcussion (five impacts, 24-hours apart), or sham (no impact) injury. The repeat subconcussive injury was patterned following preliminary data from our lab. Female rats received the first impact on the day of proestrus, when estrogen concentrations peak during the estrous cycle. Behavioral tests were administered two hours post impact through 31 days post-injury. All animals with a single concussion or repeat subconcussion showed deficits in locomotion, righting reflexes, and recognition memory, while animals with a single subconcussion did not. Repeat subconcussions produced deficits similar to a single concussion in righting reflex and recognition memory, but locomotor deficits were greater in rats with repeat subconcussions. When assessing sex differences in the behavioral responses to the repeat subconcussive model, female rats showed greater deficits than males in righting reflexes, locomotion, and vestibular function. Males showed greater increases in anxiety-like behaviors than the females. This study established a model of subconcussive impact where a single subconcussive impact resulted in little to no behavioral deficits but repeat subconcussive impacts resulted in deficits that are similar to or worse than a single concussion. Our data also suggest that females may experience more deleterious effects in certain outcomes following both concussive and subconcussive impacts, which supports some clinical findings. Further experiments will need to be done to examine sex differences in the neuropathology