Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence.

The transition from recreational drug use to addiction involves pathological learning processes that support a persistent shift from flexible, goal-directed to habit behavioral control. Here, we examined the molecular mechanisms supporting altered function in hippocampal (HPC) and dorsolateral striatum (DLS) memory systems following abstinence from repeated cocaine. After 3 weeks of cocaine abstinence (experimenter- or self-administered), we tested new behavioral learning in male rats using a dual-solution maze task, which provides an unbiased approach to assess HPC- versus DLS-dependent learning strategies. Dorsal hippocampus (dHPC) and DLS brain tissues were collected after memory testing to identify transcriptional adaptations associated with cocaine-induced shifts in behavioral learning. Our results demonstrate that following prolonged cocaine abstinence rats show a bias toward the use of an inflexible, habit memory system (DLS) in lieu of a more flexible, easily updated memory system involving the HPC. This memory system bias was associated with upregulation and downregulation of brain-derived neurotrophic factor (BDNF) gene expression and transcriptionally permissive histone acetylation (acetylated histone H3, AcH3) in the DLS and dHPC, respectively. Using viral-mediated gene transfer, we overexpressed BDNF in the dHPC during cocaine abstinence and new maze learning. This manipulation restored HPC-dependent behavioral control. These findings provide a system-level understanding of altered plasticity and behavioral learning following cocaine abstinence and inform mechanisms mediating the organization of learning and memory more broadly

Some current ideas about the evolution of the human life history

Journal ArticleHuman life history is characterised by a long juvenile period (weaning to reproductive maturity), and a long post-reproductive lifespan in females. How do we explain the differences between our nearest relatives, the great apes, and ourselves? This chapter summarises some recent attempts to use life history models on data from contemporary hunter-gatherers, and other noncontracepting populations with little access to modern medicine

Hadza scavenging: implications for Plio/Pleistocene Hominid subsistence

Journal ArticleThe frequent association of stone tools and large animal bones in African Plio/Pleistocene archaeological sites has long been taken as evidence of the importance of hunting in early hominid diets. Many now argue that it reflects hominid scavenging, not hunting

Global process and local ecology: how should we explain differences between the Hadza and the !Kung?

Journal ArticleIn this chapter we discuss explanations for the diversity of behavior of contemporary forager populations. Other contributors document variation among southern African savanna Bushman groups, and central African forest Pygmies. We confine ourselves to trying to explain some differences between two savanna groups who have been studied quantitatively, the Hadza and the !Kung. We further confine ourselves to discussing two kinds of explanation that are currently considered to be opposed to one another, behavioral ecology (Smith and Winterhalder 1992), and political economy/historical revisionism as presented to hunter-gatherer researchers by Wilmsen (1989)

Hunting and nuclear families: some lessons from the Hadza about men's work

Journal ArticleHadza hunter-gatherers display economic and social features usually assumed to indicate the dependence of wives and children on provisioning husbands and fathers. The wives and children of better Hadza hunters have been found to be better-nourished, consistent with the assumption that men hunt to provision their families. Yet, as is common among foragers, the Hadza share meat widely. Analyses of meat-sharing data confirm that little of the meat from large prey went to the hunter's own household. These analyses also show that neither a man's hunting success nor the time he spent hunting made any difference in how much meat his family got from the kills of others. Here we address questions posed by this set of observations. What explains the better nutrition of the children of better hunters if they did not get differential rations of meat? If better hunters got no more meat for their effort and poorer hunters were not punished with less, what incentive could account for the continuing disproportionate contribution that some men made to the group's nutrition? If women were not dependent on their husband's hunting success for meat, an obvious incentive for women to marry hunters disappears. We briefly consider the implications of these patterns for the evolution of marriage and nuclear families

Hadza children's foraging: juvenile dependency, social arrangement and mobility among hunter-gatherers

Journal ArticlePresents a study on the foraging activities of Hadza children in Tanzania, Africa. Success of children's foraging; Determinants of children's foraging; Monitoring of the activities of children; Near-camp foraging return rates; Variables underlying the patterns of foraging

Hadza women's time allocation, offspring provisioning, and the evolution of long postmenopausal life spans

Journal ArticleExtended provisioning of offspring and long postmenopausal life spans are characteristic of all modern humans but no other primates. These traits may have evolved in tandem. Analysis of relationships between women's time allocation and children's nutritional welfare among the Hadza of northern Tanzania yields results consistent with this proposition. Implications for current thought about the evolution of hominid food sharing, life history, and social organization are discussed. [ABSTRACT FROM AUTHOR

When fecundity does not equal fitness: evidence of an offspring quantity versus quality trade-off in pre-industrial humans

Maternal fitness should be maximized by the optimal division of reproductive investment between offspring number and offspring quality. While evidence for this is abundant in many taxa, there have been fewer tests in mammals, and in particular, humans. We used a dataset of humans spanning three generations from pre-industrial Finland to test how increases in maternal fecundity affect offspring quality and maternal fitness in contrasting socio-economic conditions. For ‘resource-poor’ landless families, but not ‘resource-rich’ landowning families, maternal fitness returns diminished with increased maternal fecundity. This was because the average offspring contribution to maternal fitness declined with increased maternal fecundity for landless but not landowning families. This decline was due to reduced offspring recruitment with increased maternal fecundity. However, in landowning families, recruited offspring fecundity increased with increased maternal fecundity. This suggests that despite decreased offspring recruitment, maternal fitness is not reduced in favourable socio-economic conditions due to an increase in subsequent offspring fecundity. These results provide evidence consistent with an offspring quantity–quality trade-off in the lifetime reproduction of humans from poor socio-economic conditions. The results also highlight the importance of measuring offspring quality across their whole lifespan to estimate reliably the fitness consequences of increased maternal fecundity

Concise review: can stem cells be used to treat or model Alzheimer’s disease

Abstract Alzheimer disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States alone. AD patients suffer from progressive neurodegeneration that gradually impairs their memory, ability to learn, and carry out daily activities. Unfortunately, current therapies for AD are largely palliative and several promising drug candidates have failed in recent clinical trials. There is therefore an urgent need to improve our understanding of AD pathogenesis, create innovative and predictive models, and develop new and effective therapies. In this review we will discuss the potential of stem cells to aid in these challenging endeavors. Because of the widespread nature of AD pathology, cell replacement strategies have been viewed as an incredibly challenging and unlikely treatment approach. Yet, recent work shows that transplantation of neural stem cells (NSCs) can improve cognition, reduce neuronal loss, and enhance synaptic plasticity in animal models of AD. Interestingly, the mechanisms that mediate these effects appear to involve neuroprotection and trophic support rather than neuronal replacement. Stem cells may also offer a powerful new approach to model and study AD. Patient-derived induced pluriptotent stem cells (iPSCs), for example, may help to advance our understanding of disease mechanisms. Likewise, studies of human embryonic and neural stem cells are helping to decipher the normal functions of AD-related genes; revealing intriguing roles in neural development

Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice.

BackgroundAlzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification.MethodsA combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays.ResultsT5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice.ConclusionsAV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD