It has been approximately 30 years since the seminal discoveries of David Barker and his colleagues, and research is beginning to unravel the mechanisms that underlie developmental programming. The early environment of the embryo, foetus and newborn have been clearly linked to altered hypothalamic-pituitary-adrenal (HPA) function and related behaviours through the juvenile period and into adulthood. A number of recent studies have shown that these effects can pass across multiple generations. The HPA axis is highly responsive to the environment, impacts both central and peripheral systems and is critical to health in a wide variety of contexts. Mechanistic studies in animals are linking early exposures to adversity with changes in gene regulatory mechanisms, including modifications of DNA methylation and altered levels of miRNA. Similar associations are emerging from recent human studies. These findings suggest that epigenetic mechanisms represent a fundamental link between adverse early environments and developmental programming of later disease. The underlying biological mechanisms that connect the perinatal environment with modified long-term health outcomes represent an intensive area of research. Indeed, opportunities for early interventions must identify the relevant environmental factors and their molecular targets. This new knowledge will likely assist in the identification of individuals who are at risk of developing poor outcomes and for whom early intervention is most effective.

/pdf/developmental-programming-of-the-hpa-axis-and-related-5f51hdrywz.pdf

Developmental programming of the HPA axis and related behaviours: epigenetic mechanisms

Brain-derived neurotrophic factor (BDNF), a critical member of the neurotrophic family, plays an important role in multiple stress-related mental disorders. Although alterations in BDNF in multiple brain regions of individuals experiencing stress have been demonstrated in previous studies, it appears that a set of elements are involved in the complex regulation. In this review, we summarize the specific brain regions with altered BDNF expression during stress exposure. How various environmental factors, including both physical and psychological stress, affect the expression of BDNF in specific brain regions are further summarized. Moreover, epigenetic regulation of BDNF, including DNA methylation, histone modification, and noncoding RNA, in response to diverse types of stress, as well as sex differences in the sensitivity of BDNF to the stress response, is also summarized. Clarification of the underlying role of BDNF in the stress process will promote our understanding of the pathology of stress-linked mental disorders and provide a potent target for the future treatment of stress-related illness.

https://www.mdpi.com/1422-0067/21/4/1375/pdf

The Relationships Between Stress, Mental Disorders, and Epigenetic Regulation of BDNF.

Maternal stressors and the developmental origins of neuropsychiatric risk.

Although most humans will experience some type of traumatic event in their lifetime only a small set of individuals will go on to develop post-traumatic stress disorder (PTSD). Differences in sex, age, trauma type, and comorbidity, along with many other elements, contribute to the heterogenous manifestation of this disorder. Nonetheless, aberrant hypothalamus-pituitary-adrenal (HPA) axis activity, especially in terms of cortisol and glucocorticoid receptor (GR) alterations, has been postulated as a tenable factor in the etiology and pathophysiology of PTSD. Moreover, emerging data suggests that the harmful effects of traumatic stress to the HPA axis in PTSD can also propagate into future generations, making offspring more prone to psychopathologies. Predator stress models provide an ethical and ethologically relevant way to investigate tentative mechanisms that are thought to underlie this phenomenon. In this review article, we discuss findings from human and laboratory predator stress studies that suggest changes to DNA methylation germane to GRs may underlie the generational effects of trauma transmission. Understanding mechanisms that promote stress-induced psychopathology will represent a major advance in the field and may lead to novel treatments for such devastating, and often treatment-resistant trauma and stress-disorders.

/pdf/stress-across-generations-dna-methylation-as-a-potential-4vdelut3at.pdf

Stress Across Generations: DNA Methylation as a Potential Mechanism Underlying Intergenerational Effects of Stress in Both Post-traumatic Stress Disorder and Pre-clinical Predator Stress Rodent Models.

The widespread consumption of 'western'-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome.

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity.

Perinatal high fat diet induces early activation of endocrine stress responsivity and anxiety-like behavior in neonates.

Maternal stress has a profound impact on the long-term behavioral phenotype of offspring, including behavioral responses to stressful and social situations. In this study, we examined the effects of maternal exposure to predator odor, an ethologically relevant psychogenic stressor, on stress-induced behaviors in both semi-naturalistic and laboratory-based situations. Adult C57BL/6 mice offspring of dams exposed to predator odor during the last half of pregnancy showed increased anti-predatory behavior, more cautious foraging behavior and, in the elevated plus maze, avoidance of elevated open areas and elevated open areas following restraint stress challenge. These offspring also exhibited alterations in social behavior including reduced free interaction and increased initial investigation despite normal social recognition. These changes in behavior were associated with increased transcript abundance of corticotropin-releasing factor, mineralocorticoid receptor and oxytocin (Oxt) in the periventricular nucleus of the hypothalamus. Taken together, the findings are consistent with a long-term increase in ethologically-relevant behavioral and neural responses to stress in male and female offspring as a function of maternal predator odor exposure.

/pdf/maternal-predator-odor-exposure-in-mice-programs-adult-45go08esvr.pdf

Maternal Predator Odor Exposure in Mice Programs Adult Offspring Social Behavior and Increases Stress-Induced Behaviors in Semi-Naturalistic and Commonly-Used Laboratory Tasks.

Orexin neurons are sensitive to CO2 and contribute to cardiorespiratory homeostasis as well as sensorimotor control. Whether orexin facilitates respiratory and behavioral responses to acute hypoxia is unclear. We hypothesized that orexin neurons are activated by acute hypoxia and that orexin facilitates the hypoxic ventilatory response (HVR), as well as the arterial blood pressure (ABP) and behavioral (movement) responses to acute hypoxia. We further hypothesized that orexin has greater effects in the active phase of the rat circadian cycle, when orexin neurons have high activity. Using whole-body plethysmography with EEG, EMG and the dual-orexin receptor (OxR) antagonist suvorexant (20 mg/kg, i.p.), we determined the effect of OxR blockade on the respiratory, ABP and behavioral responses of adult rats to acute, graded hypoxia (FIO2=0.15, 0.13, 0.11 and 0.09) and hyperoxic hypercapnia (FICO2=0.05; FIO2=0.95). OxR blockade had no effect on eupnea. OxR blockade significantly reduced the HVR in both inactive and active phases, with a stronger effect in the active phase. OxR blockade reduced the behavioral response to acute hypoxia in the active phase. The central component of the ventilatory and the ABP responses to hypercapnia were reduced by OxR blockade solely the inactive phase. In the inactive phase, hypoxia activated ~10% of orexin neurons in the perifornical hypothalamus. These data suggest that orexin neurons participate in the peripheral chemoreflex to facilitate the ventilatory and behavioral responses to acute hypoxia in rats, particularly in the active phase. Orexin also facilitates central chemoreflex responses to CO2 in the inactive phase.

Orexin facilitates the ventilatory and behavioral responses of rats to hypoxia.

Opioids provide analgesia, as well as modulate sleep and respiration, all by possibly acting on the μ-opioid receptors (MOR). MOR’s are ubiquitously present throughout the brain, posing a challenge for understanding the precise anatomical substrates that mediate opioid induced respiratory depression (OIRD) that ultimately kills most users. Sleep is a major modulator not only of pain perception, but also for changing the efficacy of opioids as analgesics. Therefore, sleep disturbances are major risk factors for developing opioid overuse, withdrawal, poor treatment response for pain, and addiction relapse. Despite challenges to resolve the neural substrates of respiratory malfunctions during opioid overdose, two main areas, the pre-Bötzinger complex (preBötC) in the medulla and the parabrachial (PB) complex have been implicated in regulating respiratory depression. More recent studies suggest that it is mediation by the PB that causes OIRD. The PB also act as a major node in the upper brain stem that not only receives input from the chemosensory areas in medulla, but also receives nociceptive information from spinal cord. We have previously shown that the PB neurons play an important role in mediating arousal from sleep in response to hypercapnia by its projections to the forebrain arousal centers, and it may also act as a major relay for the pain stimuli. However, due to heterogeneity of cells in the PB, their precise roles in regulating, sleep, analgesia, and respiratory depression, needs addressing. This review sheds light on interactions between sleep and pain, along with dissecting the elements that adversely affects respiration.

/pdf/opioids-sleep-analgesia-and-respiratory-depression-their-3spefw5t.pdf

Opioids, sleep, analgesia and respiratory depression: Their convergence on Mu (μ)-opioid receptors in the parabrachial area

Orexin neurons project to nuclei participating in the hypoxic ventilatory response (HVR), including to the nucleus tractus solitarius (nTS) and paraventricular nucleus of the hypothalamus (PVN), nuclei that also express orexin receptors (OxRs). Many nTS‐projecting PVN neurons that are activated by acute hypoxia (Hx) are also immunoreactive (IR) for corticotropin‐releasing hormone (CRH). Orexin neurons are active in the dark (active) phase and silent in the light (inactive) phase. Orexin contributes to the HVR in males, especially in the dark phase. The possibility that orexin neurons facilitate the HVR through pathways that involve the PVN and/or nTS has not been investigated. Whether orexin influences the HVR in females is also unknown. This is a relevant issue because recent data suggest that orexin neurons are potently inhibited by estrogen. Here we hypothesized that orexin: 1) facilitates the HVR in females, especially during diestrus (i.e., low estrogen) in the dark phase, and 2) contributes to the HVR by facilitating the activation of CRH neurons in the PVN and/or neurons in the nTS. We tested these hypotheses using adult female and male Sprague Dawley rats (age 3‐4 months) and whole‐body plethysmography to measure ventilation (VE) during normoxia and hypoxia. Daily vaginal smears were performed to determine the stage of estrus cycle. Female rats (n=4) were exposed to graded hypoxia (FIO2from 0.21 to 0.09) over 3‐5 minutes to avoid the effects of hypoxia on body temperature and metabolic rate. Each rat was tested after vehicle and again following suvorexant (a dual OxR antagonist; 20 mg/kg, i.p.). Each rat was tested during proestrus/estrus and again in diestrus. The same rats were tested in the dark phase and then approximately 2 weeks later in the light phase. We measured the effects OxR blockade on VE during normoxia and at FIO2=0.15, 0.13, 0.11 and 0.09 (at least five breaths at each level), as well as on metabolic CO2 production (VCO2) in normoxia. Male rats were exposed to hypoxia (FIO2=0.11; n=4) or normoxia (n=4) for 2 hrs in the dark phase, after either suvorexant or vehicle, in order to induce c‐Fos expression. Immunofluorescence was performed to quantify the activation (i.e., Fos‐IR) of the PVN (particularly CRH neurons) and nTS neurons. During estrus, the HVR (determined by the increase in VE/VCO2) was slightly reduced following OxR blockade in the dark phase (drug: p=0.022). The inhibitory effect of OxR blockade on the HVR in the dark phase was much stronger during diestrus (by ~50% at FIO2=0.11; O2 level x drug: p=0.006). In the light phase there was no significant effect of OxR blockade on the HVR, regardless of estrus cycle stage. In male rats, OxR blockade significantly reduced the number of activated CRH PVN neurons (by ~50%; drug: p=0.012), and nTS neurons (by ~50%; drug x O2 level: p=0.027). Thus, orexin contributes to the HVR in females, especially during diestrus in the dark phase, when orexin neurons presumably have their highest activity. Orexin may facilitate the peripheral chemoreflex via pathway(s) that involve both the nTS and CRH neurons in the PVN.

Richard L. Spinieli

Papers

Perinatal high fat diet induces early activation of endocrine stress responsivity and anxiety-like behavior in neonates.

Maternal Predator Odor Exposure in Mice Programs Adult Offspring Social Behavior and Increases Stress-Induced Behaviors in Semi-Naturalistic and Commonly-Used Laboratory Tasks.

Orexin facilitates the ventilatory and behavioral responses of rats to hypoxia.

Opioids, sleep, analgesia and respiratory depression: Their convergence on Mu (μ)-opioid receptors in the parabrachial area

Orexin Facilitates the Hypoxic Ventilatory Response: Influence of Estrus Cycle