Long-term male-specific chronic pain via telomere- and p53­mediated spinal cord cellular senescence.

Mice with experimental nerve damage can display long­lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53­mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53­positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male­specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male­specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53­specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male­specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.

Social propinquity in rodents as measured by tube cooccupancy differs between inbred and outbred genotypes.

Existing assays of social interaction are suboptimal, and none measures propinquity, the tendency of rodents to maintain close physical proximity. These assays are ubiquitously performed using inbred mouse strains and mutations placed on inbred genetic backgrounds. We developed the automatable tube cooccupancy test (TCOT) based on propinquity, the tendency of freely mobile rodents to maintain close physical proximity, and assessed TCOT behavior on a variety of genotypes and social and environmental conditions. In outbred mice and rats, familiarity determined willingness to cooccupy the tube, with siblings and/or cagemates of both sexes exhibiting higher cooccupancy behavior than strangers. Subsequent testing using multiple genotypes revealed that inbred strain siblings do not cooccupy at higher rates than strangers, in marked contrast to both outbred and rederived wild mice. Mutant mouse strains with "autistic-like" phenotypes (Fmr1-/y and Eif4e Ser209Ala) displayed significantly decreased cooccupancy.

Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury.

Spinal cord injury (SCI) leads to increased anxiety and depression in as many as 60% of patients. Yet, despite extensive clinical research focused on understanding the variables influencing psychological well-being following SCI, risk factors that decrease it remain unclear. We hypothesized that excitation of the immune system, inherent to SCI, may contribute to the decrease in psychological well-being. To test this hypothesis, we used a battery of established behavioral tests to assess depression and anxiety in spinally contused rats. The behavioral tests, and subsequent statistical analyses, revealed three cohorts of subjects that displayed behavioral characteristics of (1) depression, (2) depression and anxiety, or (3) no signs of decreased psychological well-being. Subsequent molecular analyses demonstrated that the psychological cohorts differed not only in behavioral symptoms, but also in peripheral (serum) and central (hippocampi and spinal cord) levels of pro-inflammatory cytokines. Subjects exhibiting a purely depression-like profile showed higher levels of pro-inflammatory cytokines peripherally, whereas subjects exhibiting a depression- and anxiety-like profile showed higher levels of pro-inflammatory cytokines centrally (hippocampi and spinal cord). These changes in inflammation were not associated with injury severity; suggesting that the association between inflammation and the expression of behaviors characteristic of decreased psychological well-being was not confounded by differential impairments in motor ability. These data support the hypothesis that inflammatory changes are associated with decreased psychological well-being following SCI.

Psychological stress as a modulator of functional recovery following spinal cord injury.

There is strong evidence indicating that the social environment triggers changes to the psychological stress response and glucocorticoid receptor function. Considerable literature links the subsequent changes in stress resiliency to physical health. Here, converging evidence for the modulatory role of chronic psychological stress in the recovery process following spinal cord injury (SCI) is presented. Despite the considerable advances in SCI research, we are still unable to identify the causes of variability in patients' recovery following injury. We propose that individuals' past and present life experiences (in the form of stress exposure) may significantly modulate patients' outcome post-SCI. We propose a theoretical model to explain the negative impact of chronic psychological stress on physical and psychological recovery. The stress experienced in life prior to SCI and also as a result of the traumatic injury, could compromise glucocorticoid receptor sensitivity and function, and contribute to high levels of inflammation and apoptosis post-SCI, decreasing the tissue remaining at the injury site and undermining recovery of function. Both stress-induced glucocorticoid resistance and stress-induced epigenetic changes to the glucocorticoid receptor can modulate the nuclear factor-kappa B regulated inflammatory pathways and the Bcl-2 regulated apoptosis pathways. This model not only contributes to the theoretical understanding of the recovery process following injury, but also provides concrete testable hypotheses for future studies.

The forsaken mental health of the Indigenous Peoples - a moral case of outrageous exclusion in Latin America.

BACKGROUND: Mental health is neglected in most parts of the world. For the Indigenous Peoples of Latin America, the plight is even more severe as there are no specific mental health services designed for them altogether. Given the high importance of mental health for general health, the status quo is unacceptable. Lack of research on the subject of Indigenous Peoples' mental health means that statistics are virtually unavailable. To illustrate their mental health status, one can nonetheless point to the high rates of poverty and extreme poverty in their communities, overcrowded housing, illiteracy, and lack of basic sanitary services such as water, electricity and sewage. At the dawn of the XXI century, they remain poor, powerless, and voiceless. They remain severely excluded from mainstream society despite being the first inhabitants of this continent and being an estimated of 48 million people. This paper comments, specifically, on the limited impact of the Pan American Health Organization's mental health initiative on the Indigenous Peoples of Latin America. DISCUSSION: The Pan American Health Organization's sponsored workshop "Programas y Servicios de Salud Mental en Communidades Indígenas" [Mental Health Programs and Services for the Indigenous Communities] in the city of Santa Cruz, Bolivia on July16 - 18, 1998, appeared promising. However, eleven years later, no specific mental health program has been designed nor developed for the Indigenous Peoples in Latin America. This paper makes four specific recommendations for improvements in the approach of the Pan American Health Organization: (1) focus activities on what can be done; (2) build partnerships with the Indigenous Peoples; (3) consider traditional healers as essential partners in any mental health effort; and (4) conduct basic research on the mental health status of the Indigenous Peoples prior to the programming of any mental health service. SUMMARY: The persistent neglect of the Indigenous Peoples' mental health in Latin America raises serious concerns of moral and human rights violations. Since the Pan American Health Organization' Health of the Indigenous Peoples Initiative 16 years ago, no mental health service designed for them has yet been created.