The impact of adolescent stress on nicotine use and affective disorders in rodent models.

Recent findings indicate that stress exposure during adolescence contributes to the development of both nicotine use and affective disorders, suggesting a potential shared biological pathway. One key system that may mediate the association between adolescent stress and nicotine or affective outcomes is the hypothalamic-pituitary-adrenal (HPA) axis. Here we reviewed evidence regarding the effects of adolescent stress on nicotine responses and affective phenotypes and the role of the HPA-axis in these relationships. Literature indicates that stress, possibly via HPA-axis dysfunction, is a risk factor for both nicotine use and affective disorders. In rodent models, adolescent stress modulates behavioural responses to nicotine and increases the likelihood of affective disorders. The exact role that the HPA-axis plays in altering nicotine sensitivity and affective disorder development after adolescent stress remains unclear. However, it appears likely that adolescent stress-induced nicotine use and affective disorders are precipitated by repetitive activation of a hyperactive HPA-axis. Together, these preclinical studies indicate that adolescent stress is a risk factor for nicotine use and anxiety/depression phenotypes. The findings summarized here suggest that the HPA-axis mediates this relationship. Future studies that pharmacologically manipulate the HPA-axis during and after adolescent stress are critical to elucidate the exact role that the HPA-axis plays in the development of nicotine use and affective disorders following adolescent stress.

Genetic Differences in Dorsal Hippocampus Acetylcholinesterase Activity Predict Contextual Fear Learning Across Inbred Mouse Strains.

Learning is a critical behavioral process that is influenced by many neurobiological systems. We and others have reported that acetylcholinergic signaling plays a vital role in learning capabilities, and it is especially important for contextual fear learning. Since cholinergic signaling is affected by genetic background, we examined the genetic relationship between activity levels of acetylcholinesterase (AChE), the primary enzyme involved in the acetylcholine metabolism, and learning using a panel of 20 inbred mouse strains. We measured conditioned fear behavior and AChE activity in the dorsal hippocampus, ventral hippocampus, and cerebellum. Acetylcholinesterase activity varied among inbred mouse strains in all three brain regions, and there were significant inter-strain differences in contextual and cued fear conditioning. There was an inverse correlation between fear conditioning outcomes and AChE levels in the dorsal hippocampus. In contrast, the ventral hippocampus and cerebellum AChE levels were not correlated with fear conditioning outcomes. These findings strengthen the link between acetylcholine activity in the dorsal hippocampus and learning, and they also support the premise that the dorsal hippocampus and ventral hippocampus are functionally discrete.

The effects of neonatal procedural pain and maternal isolation on hippocampal cell proliferation and reelin concentration in neonatal and adult male and female rats.

Preterm births accounted for over 10% of all U.S. live births in 2019 and the rate is rising. Neonatal stressors, especially procedural pain, experienced by preterm infants in the neonatal intensive care unit (NICU) have been associated with neurodevelopmental impairments. Parental care can alleviate stress during stressful or painful procedures; however, infants in the NICU often receive reduced parental care compared with their peers. Animal studies suggest that decreased maternal care similarly impairs neurodevelopment but also influences the effects of neonatal pain. It is important to mimic both stressors in animal models of neonatal stress exposure. In this study, researchers investigated the individual and combined impact of neonatal pain and maternal isolation on reelin protein levels and cellular proliferation in the hippocampal dentate gyrus of 8 days old and adult rats. Exposure to either stressor individually, but not both, increased reelin levels in the dentate gyrus of adult females without significantly altering reelin levels in adult males. However, cell proliferation levels at either age were unaffected by the early-life stressors. These results suggest that each early-life stressor has a unique effect on markers of brain development and more research is needed to further investigate their distinct influences.

Probiotic treatment (Bifidobacterium longum subsp. longum 35624™) affects stress responsivity in male rats after chronic corticosterone exposure.

Mounting evidence suggests that gut microbiota do not only regulate intestinal function and health, but that they also play a role in mental health via the gut-brain axis. Previous research further suggests that probiotics may have beneficial health effects, but more research is needed to confirm these beneficial effects and better understand the underlying mechanisms and potential sex differences in the response to probiotics. Therefore, the current study investigates the effects of chronic administration of the commercially available probiotic Bifidobacterium longum subsp. longum 35624™(B. 35624) to male and female rats under control or "stressed" conditions. For this, 24 male and 24 female Sprague-Dawley rats were either given daily corticosterone injections (40 mg/kg; to induce depressive-like behavior and a "stressed" condition) or oil injections (controls) together with oral administration of B.35624 or vehicle for 21 days (n = 5-7/group). Animals performed the Open Field Test (OFT) and Forced Swim Test (FST) and several blood samples were collected to investigate basal as well as stress-induced corticosterone levels. Rats were sacrificed on day 22 and their brains sliced and stained with doublecortin, a marker of immature neurons. Results showed that B.35624 was not able to rescue depressive-like behavior or induce changes in neurogenesis in males or females, but the probiotic impacted hypothalamic-pituitary-adrenal axis functioning in male animals and tended to reduce anxiolytic behavior in the OFT. More research is needed to further elucidate the potential health effects of probiotics especially in regard to possible sex differences.

Neonatal pain and reduced maternal care alter adult behavior and hypothalamic-pituitary-adrenal axis reactivity in a sex-specific manner.

Preterm infants often spend a significant amount of time in the neonatal intensive care unit (NICU) where they are exposed to many stressors including pain and reduced maternal care. These early-life stressful experiences can have negative consequences on brain maturation during the neonatal period; however, less is known about the long-term cognitive and affective outcomes. Thus, this study was conducted to investigate the impact of neonatal pain and reduced maternal care on adult behavior and HPA axis reactivity in an animal model. Male and female rats underwent a series of repetitive needle pokes and/or reduced maternal care (through a novel tea ball infuser encapsulation method) during the first 4 days of life and were then assessed in a battery of behavioral tests as adults. We found that early-life pain enhanced spatial learning independent of the animal's sex, but altered HPA recovery from an acute stressor in females only. Moreover, reduced maternal care altered long-term spatial memory and reversal learning in males. These findings indicate that neonatal stressors have unique sex-dependent long-term biobehavioral effects in rodents. Continued examination of the behavioral consequences of these stressors may help explain varying vulnerability and resiliency in preterm infants who experienced early stress in the NICU.

Developmental outcomes after gestational antidepressant treatment with sertraline and its discontinuation in an animal model of maternal depression.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to women before or during pregnancy to manage their depressive symptoms. However, there is still little knowledge regarding the long-term development effects of SSRI exposure for the fetus or the effects of discontinuing SSRI treatment during pregnancy. This study utilized a translational animal model of maternal depression (based on giving high levels of corticosterone (CORT, 40 mg/kg, s.c.) or vehicle (Oil) for 21 days prior to conception) to investigate the effects of sertraline (a frequently prescribed SSRI; 20 mg/kg p.o., treatment started ∼7 days prior to conception) and its discontinuation during pregnancy (on gestational day 16) compared to vehicle (water) treatment on the development of the offspring. Our results revealed that both corticosterone exposure prior to pregnancy and sertraline administration and its discontinuation during gestation had sex-specific effects on behavior in the adult offspring. In particular, pre-conceptional maternal corticosterone treatment impacted the stress response, anxiety-like behavior and cognitive performance in adult female offspring, while gestational SSRI exposure and its discontinuation compared to full-term exposure affected impulsivity in females, and exploratory behavior in males. More research is needed on the effects of exposure to antidepressant medication and its discontinuation compared to depression during pregnancy and how each impacts development to better help women make informed decisions about their medication use during pregnancy.

Repetitive neonatal pain and reduced maternal care alter brain neurochemistry.

Preterm infants are exposed to many stressors while in the neonatal intensive care unit including pain and reduced maternal care. Both stressors can have a profound negative impact on brain development, and the present study sought to investigate some of the biological mechanisms underlying this phenomenon. Rat pups underwent a series of repetitive needle pokes and/or reduced maternal care through a novel tea-ball infuser encapsulation model during the first four days of life. On postnatal day four, pups were sacrificed and serum was analyzed for corticosterone, while brains were tested for various neurotransmitters and brain metabolites through magnetic resonance spectroscopy. We found that exposure to maternal isolation and neonatal pain produced an increase in serum corticosterone but decreased glutamate levels in the hippocampus and frontal cortex. These alterations in stress responding and neurochemistry in response to the early-life stressors may help explain some of the negative outcomes seen in preterm infants.

The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse.

During adolescence, the brain continues to undergo vital developmental processes. In turn, complex behavioral and cognitive skills emerge. Unfortunately, neurobiological development during adolescence can be influenced by environmental factors such as drug exposure. Engaging in drug use during adolescence has been a long-standing health concern, especially how it predicts or relates to drug using behavior later in life. However, recent findings suggest that other behavioral domains, such as learning and memory, are also vulnerable to adolescent drug use. Moreover, it is becoming increasingly apparent that deficits in learning and memory following adolescent drug use endure into adulthood, well after drug exposure has subsided. Although persistent effects suggest an interaction between drug exposure and ongoing development during adolescence, the exact acute and long-term consequences of adolescent drug exposure on substrates of learning and memory are not fully understood. Thus, this review will summarize human and animal findings on the enduring cognitive deficits due to adolescent drug exposure. Moreover, due to the fact that adolescents are more likely to consume drugs of abuse legally available to adults, this review will focus on alcohol, nicotine, and marijuana. Further, given the critical role of the frontal cortex and hippocampus in various learning and memory domains, the impact adolescent use of the previous listed drugs on the neurobiology within these regions will also be discussed.

Neonatal pain and reduced maternal care: Early-life stressors interacting to impact brain and behavioral development.

Advances in neonatal intensive care units (NICUs) have drastically increased the survival chances of preterm infants. However, preterm infants are still exposed to a wide range of stressors during their stay in the NICU, which include painful procedures and reduced maternal contact. The activation of the hypothalamic-pituitary-adrenal (HPA) axis, in response to these stressors during this critical period of brain development, has been associated with many acute and long-term adverse biobehavioral outcomes. Recent research has shown that Kangaroo care, a non-pharmacological analgesic based on increased skin-to-skin contact between the neonate and the mother, negates the adverse outcomes associated with neonatal pain and reduced maternal care, however the biological mechanism remains widely unknown. This review summarizes findings from both human and rodent literature investigating neonatal pain and reduced maternal care independently, primarily focusing on the role of the HPA axis and biobehavioral outcomes. The physiological and positive outcomes of Kangaroo care will also be discussed in terms of how dampening of the HPA axis response to neonatal pain and increased maternal care may account for positive outcomes associated with Kangaroo care.

The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.

Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs.

Assessment of attention in male and female Brattleboro rats using a self-paced five-choice serial reaction time task.

The Brattleboro rat is a mutant variation of the Long-Evans strain that exhibits negligible central nervous system levels of vasopressin, a neuropeptide that may influence behavioral and cognitive processes. Compared to Long-Evans rats, Brattleboro rats exhibit diminished fear conditioning and have impairments in spatial memory and sensory gating. The present study sought to further evaluate the cognitive profile of vasopressin-deficient rats by studying attention in male and female Brattleboro and heterozygous rats using a self-paced version of the five-choice serial reaction time task. Male Brattleboro rats required significantly more sessions to meet the training criteria than those by heterozygotic and Long-Evans (wild type) rats. Female Brattleboro rats displayed significantly poorer attention accuracy compared to heterozygotic and Long-Evans rats. Taken together, the present findings add further evidence that vasopressin deficiency diminishes cognitive functioning.