Early-life adversity and neurological disease: age-old questions and novel answers.

Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

Recent studies have demonstrated that paternal stress in rodents can result in modification of offspring behavior. Environmental enrichment, which enhances cognitive stimulation and physical activity, modifies various behaviors and reduces stress responses in adult rodents. We investigated the transgenerational influence of paternal environmental enrichment on offspring behavior and physiological stress response. Adult C57BL/6J male mice (F0) were exposed to either environmental enrichment or standard housing for four weeks and then pair-mated with naïve females. The F2 generation was generated using F1 male offspring. Male and female F1 and F2 offspring were tested for anxiety using the elevated-plus maze and large open field at 8 weeks of age. Depression-related behavior was assessed using the forced-swim test. Hypothalamic-pituitary-adrenal (HPA) axis function was determined by quantification of serum corticosterone and adrenocorticotropic hormone (ACTH) levels at baseline and after forced-swim stress. Paternal environmental enrichment was associated with increased body weights of male F1 and F2 offspring. There was no significant effect on F1 offspring anxiety and depression-related behaviors. There were no changes in anxiety-related behaviors in the F2 offspring, however these mice displayed a reduced latency to immobility in the forced-swim test. Furthermore, F2 females had significantly higher serum corticosterone levels post-stress, but not ACTH. These results show that paternal environmental enrichment exerts a sex-specific transgenerational impact on the behavioral and physiological response to stress. Our findings have implications for the modelling of psychiatric disorders in rodents

Early Life Exposure to Unpredictable Parental Sensory Signals Shapes Cognitive Development Across Three Species

Exposure to early life adversity has long term consequences on cognitive function. Most research has focused on understanding components of early life adversities that contribute to later risk, including poverty, trauma, maltreatment, and neglect. Whereas these factors, in the aggregate, explain a significant proportion of emotional and cognitive problems, there are serious gaps in our ability to identify potential mechanisms by which early life adversities might promote vulnerability or resilience. Here we discuss early life exposure to unpredictable signals from the caretaker as an understudied type of adversity that is amenable to prevention and intervention. We employ a translational approach to discover underlying neurobiological mechanisms by which early life exposure to unpredictable signals sculpts the developing brain. First, we review evidence that exposure to unpredictable signals from the parent during sensitive periods impacts development of neural circuits. Second, we describe a method for characterizing early life patterns of sensory signals across species. Third, we present published and original data illustrating that patterns of maternal care predict memory function in humans, non-human primates, and rodents. Finally, implications are discussed for identifying individuals at risk so that early preventive-intervention can be provided

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity.

In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function. Early-life adversity increases hippocampal CRH expression, and blocking hippocampal CRH receptor type-1 (CRHR1) immediately following early-life adversity prevented the consequent memory and LTP defects. Here, we tested if blocking CRHR1 in young adults ameliorates early-life adversity-provoked memory deficits later in life. A weeklong course of a CRHR1 antagonist in 2-month-old male rats prevented early-life adversity-induced deficits in object recognition memory that emerged by 12 months of age. Surprisingly, whereas the intervention did not mitigate early-life adversity-induced spatial memory losses at 4 and 8 months, it restored hippocampus-dependent location memory in 12-month-old rats that experienced early-life adversity. Neither early-life adversity nor CRHR1 blockade in the adult influenced anxiety- or depression-related behaviors. Altogether, these findings suggest that cognitive deficits attributable to adversity during early-life-sensitive periods are at least partially amenable to interventions later in life

Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity.

In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function. Early-life adversity increases hippocampal CRH expression, and blocking hippocampal CRH receptor type-1 (CRHR1) immediately following early-life adversity prevented the consequent memory and LTP defects. Here, we tested if blocking CRHR1 in young adults ameliorates early-life adversity-provoked memory deficits later in life. A weeklong course of a CRHR1 antagonist in 2-month-old male rats prevented early-life adversity-induced deficits in object recognition memory that emerged by 12 months of age. Surprisingly, whereas the intervention did not mitigate early-life adversity-induced spatial memory losses at 4 and 8 months, it restored hippocampus-dependent location memory in 12-month-old rats that experienced early-life adversity. Neither early-life adversity nor CRHR1 blockade in the adult influenced anxiety- or depression-related behaviors. Altogether, these findings suggest that cognitive deficits attributable to adversity during early-life-sensitive periods are at least partially amenable to interventions later in life

Sex-dependent effects of multiple acute concurrent stresses on memory: a role for hippocampal estrogens.

Memory disruption commonly follows chronic stress, whereas acute stressors are generally benign. However, acute traumas such as mass shootings or natural disasters-lasting minutes to hours and consisting of simultaneous physical, social, and emotional stresses-are increasingly recognized as significant risk factors for memory problems and PTSD. Our prior work has revealed that these complex stresses (concurrent multiple acute stresses: MAS) disrupt hippocampus-dependent memory in male rodents. In females, the impacts of MAS are estrous cycle-dependent: MAS impairs memory during early proestrus (high estrogens phase), whereas the memory of female mice stressed during estrus (low estrogens phase) is protected. Female memory impairments limited to high estrogens phases suggest that higher levels of estrogens are necessary for MAS to disrupt memory, supported by evidence that males have higher hippocampal estradiol than estrous females. To test the role of estrogens in stress-induced memory deficits, we blocked estrogen production using aromatase inhibitors. A week of blockade protected male and female mice from MAS-induced memory disturbances, suggesting that high levels of estrogens are required for stress-provoked memory impairments in both males and females. To directly quantify 17β-estradiol in murine hippocampus we employed both ELISA and mass spectrometry and identified significant confounders in both procedures. Taken together, the cross-cycle and aromatase studies in males and females support the role for high hippocampal estrogens in mediating the effect of complex acute stress on memory. Future studies focus on the receptors involved, the longevity of these effects, and their relation to PTSD-like behaviors in experimental models

Plasticity of the Reward Circuitry After Early-Life Adversity: Mechanisms and Significance

Disrupted operation of the reward circuitry underlies many aspects of affective disorders. Such disruption may manifest as aberrant behavior including risk taking, depression, anhedonia, and addiction. Early-life adversity is a common antecedent of adolescent and adult affective disorders involving the reward circuitry. However, whether early-life adversity influences the maturation and operations of the reward circuitry, and the potential underlying mechanisms, remain unclear. Here, we present novel information using cutting-edge technologies in animal models to dissect out the mechanisms by which early-life adversity provokes dysregulation of the complex interactions of stress and reward circuitries. We propose that certain molecularly defined pathways within the reward circuitry are particularly susceptible to early-life adversity. We examine regions and pathways expressing the stress-sensitive peptide corticotropin-releasing factor (CRF), which has been identified in critical components of the reward circuitry and interacting stress circuits. Notably, CRF is strongly modulated by early-life adversity in several of these brain regions. Focusing on amygdala nuclei and their projections, we provide evidence suggesting that aberrant CRF expression and function may underlie augmented connectivity of the nucleus accumbens with fear/anxiety regions, disrupting the function of this critical locus of pleasure and reward