Neurogenesis in the adult brain from ballyhoo to sobriety

New neurons are spontaneously generated in two regions of the adult brain, the hippocampus and the subventricular zone/olfactory bulb. The objective of this thesis was to study potential implications for adult neurogenesis in Alzheimer's (AD) and Parkinson's diseases (PD). PD is characterized by degeneration of dopaminergic neurons in the substantia nigra. It has been suggested that new dopaminergic neurons are formed in the normal, adult substantia nigra. In contrast, we found no newborn dopamine neurons in the brains of normal or lesioned adult rats and mice. We also noted that some of the methods previously used to identify newborn neurons in the adult substantia nigra were unreliable. We conclude that stimulation of endogenous neurogenesis in the substantia nigra holds little promise as a treatment for PD. In AD, neuropathology is more widespread, with loss of cholinergic neurons in the basal forebrain particularly associated with memory impairment. Intact neurogenesis in the adult hippocampus is suggested to mediate certain memory processes. We investigated the effects on neurogenesis of training in different forms of hippocampus-dependent spatial memory. We discovered that continuous training in a working memory task resulted in decreased neurogenesis. Next, we studied the effects of selective lesions of hippocampal input from the medial septum. We showed that the cholinergic component of the septohippocampal projection is important for proliferation, whereas the GABAergic component regulates survival of hippocampal neural progenitors. Combined lesions dramatically decreased proliferation, survival and differentiation of newborn neurons. Lastly, we demonstrated that continuous infusion of nerve growth factor in adult rats promotes hippocampal neurogenesis. We verified that hippocampal cholinergic activity is increased shortly after initiation of NGF infusion, which likely mediates the increase in neurogenesis. In summary, we demonstrated that acetylcholine and GABA, two neurotransmitter systems affected in AD, are important for intact hippocampal neurogenesis. In addition, we propose that increased hippocampal neurogenesis may contribute to cognitive improvement following NGF treatment

The septohippocampal cholinergic system and spatial working memory in the Morris water maze.

The objective of the present study was to determine whether a systematic optimization of Morris water maze (mwm) testing parameters could reveal a significant role of the septohippocampal cholinergic system in spatial working memory. Young adult rats were lesioned using 192 IgG-saporin infused bilaterally into the medial septum. Lesions were near complete as measured by choline acetyltransferase (ChAT) activity and immunohistochemistry. Behavioral testing was performed in three phases. In the first, lesioned and unlesioned rats were trained in the mwm focusing on working memory, which was tested using novel platform locations daily. In the second phase, the optimal locations were retested with increasing intertrial intervals (ITI). In the third phase, intracerebroventricular infusions of nerve growth factor (NGF) were employed to enhance cholinergic activity of the unlesioned rats and potentially further separate group performance. Neither the standard or increased ITI resulted in a consistent significant difference in spatial working memory between groups. In addition, NGF treatment also failed to induce a significant difference in behavioral performance. In conclusion, impairments in working memory as assessed by the mwm could not be revealed despite a greater than 90% loss of hippocampal ChAT and the use of optimal testing parameters and NGF treatment

Working memory training decreases hippocampal neurogenesis.

The relationship between adult hippocampal neurogenesis and cognition appears more complex than suggested by early reports. We aimed to determine if the duration and task demands of spatial memory training differentially affect hippocampal neurogenesis. Adult male rats were trained in the Morris water maze in a reference memory task for 4 days, or alternatively working memory for either 4 or 14 days. Four days of maze training did not impact neurogenesis regardless of whether reference or working memory paradigms were used. Interestingly, 2 weeks of working memory training using a hidden platform resulted in fewer newborn hippocampal neurons compared with controls that received either cue training or no maze exposure. Stress is a well-established negative regulator of hippocampal neurogenesis. We found that maze training in general, and a working memory task in particular, increased levels of circulating corticosterone after 4 days of training. Our study indicates that working memory training over a prolonged period of time reduces neurogenesis, and this reduction may partially be mediated by increased stress

Care-seeking patterns and timely access to care among survivors of sexual violence in North Kivu, the Democratic Republic of the Congo: a retrospective file-based study

Background Sexual violence is widespread in war-torn North Kivu province in the Democratic Republic of the Congo (DRC). Timely access to care is crucial for the healing and wellbeing of survivors of sexual violence, but is problematic due to a variety of barriers. Through a better understanding of care-seeking behaviours and factors influencing timely access to care, programmes can be adapted to overcome some of the barriers faced by survivors of sexual violence. Objective The aim of this study was to describe demographics, care-seeking patterns and factors influencing timely care-seeking by survivors of sexual violence. Methods Retrospective file-based data analysis of sexual violence survivors accessing care within two Médecins Sans Frontières (MSF) programmes supporting the Ministry of Health, in North Kivu, DRC, 2014–2018. Results Most survivors (66%) sought care at specialised sexual violence clinics and a majority of the survivors were self-referred (51%). Most survivors seeking care (70%) did so within 3 days. Male survivors accessing care were significantly more likely to seek care within 3 days compared to females. All age groups under 50 years old were more likely to seek care within 3 days compared to those aged 50 years and older. Being referred by the community, a family member, mobile clinic or authorities was significantly associated with less probability of seeking care within 3 days compared to being self-referred. Conclusion Access to timely health care for survivors of sexual violence in North Kivu, DRC, is challenging and varies between different groups of survivors. Providers responding to survivors of sexual violence need to adapt models of care and awareness raising strategies to ensure that programmes are developed to enable timely access to care for all survivors. More research is needed to further understand the barriers and enablers to access timely care for different groups of survivors

Nerve growth factor promotes survival of new neurons in the adult hippocampus.

xogenously provided NGF enhances cognitive performance in impaired rodents and humans and is currently a promising compound for the treatment of dementia. To investigate whether NGF-dependent cognitive improvement may be due in part to increased hippocampal neurogenesis, adult and aged male rats were treated with NGF or vehicle intracerebroventricularly for 6 or 20 days followed by evaluation of cholinergic parameters and hippocampal neurogenesis. We show that NGF increases hippocampal cholinergic activity as rapidly as 3 days after initiation of treatment. NGF treatment for 6 days did not affect proliferation of progenitor cells in the dentate gyrus granule cell layer (GCL). However, continuous NGF infusion enhanced survival of new neurons in the GCL of young adult, but not aged rats. Taken together, these findings suggest that NGF, likely mediated through increased cholinergic tone, promotes neurogenesis in the adult hippocampus, which may relate to the nootropic action of NGF

High-fat diet impairs hippocampal neurogenesis in male rats.

High fat diets and obesity pose serious health problems, such as type II diabetes and cardiovascular disease. Impaired cognitive function is also associated with high fat intake. In this study, we show that just 4 weeks of feeding a diet rich in fat ad libitum decreased hippocampal neurogenesis in male, but not female, rats. There was no obesity, but male rats fed a diet rich in fat exhibited elevated serum corticosterone levels compared with those fed standard rat chow. These data indicate that high dietary fat intake can disrupt hippocampal neurogenesis, probably through an increase in serum corticosterone levels, and that males are more susceptible than females

Occurrence of major infectious diseases and healthcare seeking among young children with disabilities in Sierra Leone using cross-sectional population-based survey data

Background Children with disabilities are at risk of worse health outcomes compared to children without functional difficulties. Sierra Leone has one of the world’s highest prevalences of functional difficulties among children, but little is known about the co-occurrence of major infectious diseases and healthcare-seeking behaviours among children with disabilities.Methods We used household survey cross-sectional data on children 2–4 years old and logistic regression models estimating ORs between functional difficulties and symptoms of infectious diseases including diarrhoea, fever and acute respiratory infection (ARI), adjusted for sex, age and stunting. We also examined whether caregivers sought advice or treatment for the illness from any source and if the child was given any treatment for the illness.Results There was an increased risk of fever among children with functional difficulty (adjusted OR (AOR)=1.3, 95% CI 1.1 to 1.8) and children with severe functional difficulty (AOR=1.6, 95% CI 1.0 to 2.7). Children with severe functional difficulty were also at increased risk of diarrhoea (AOR=1.8, 95% CI=1.1 to 3.3). There were no significant differences in seeking advice or treatment for diarrhoea, fever or ARI symptoms between the groups.Conclusions In Sierra Leone, children with functional difficulties, especially severe functional difficulties, more often have symptoms of major childhood diseases that are known to increase under-5 mortality

Agenda 2030 och målen för en hållbar utveckling angår oss alla

The 2030 Agenda for Sustainable Development and its seventeen Sustainable Development Goals were adopted by the United Nations General Assembly in 2015. It is a bold agenda for global social, environmental and economic development, with human health as a central theme. Even though substantial improvements in health have been achieved during the last decades, every year over 5 million children die, mostly from preventable causes, and 300 000 women die in conjunction with childbirth. Premature deaths from non-communicable diseases are increasing, and our ability to treat infections is under threat through widespread anti-microbial resistance. Climate change is recognized as the biggest threat to health in our time. When the world now starts to plan for how society and our health systems should be reorganized after the COVID-19 pandemic the 2030 Agenda could and should play a central role. In this context, Agenda 2030 provides an ambitious roadmap for development, with its emphasis on collaboration across borders and disciplines. The agenda is achievable but reaching its goals will require strong commitment at all levels and societal change on a large scale

Transitional and translational studies of risk for anxiety

Adolescence reflects a period of increased rates of anxiety, depression, and suicide. Yet most teens emerge from this period with a healthy, positive outcome. In this article, we identify biological factors that may increase risk for some individuals during this developmental period by: (1) examining changes in neural circuitry underlying core phenotypic features of anxiety as healthy individuals transition into and out of adolescence; (2) examining genetic factors that may enhance the risk for psychopathology in one individual over another using translation from mouse models to human neuroimaging and behavior; and (3) examining the effects of early experiences on core phenotypic features of anxiety using human neuroimaging and behavioral approaches. Each of these approaches alone provides only limited information on genetic and environmental influences on complex human behavior across development. Together, they reflect an emerging field of translational developmental neuroscience in forming important bridges between animal models of neurodevelopmental and neuropsychiatric disorders