Addiction, Adolescence, and Innate Immune Gene Induction

Repeated drug use/abuse amplifies psychopathology, progressively reducing frontal lobe behavioral control, and cognitive flexibility while simultaneously increasing limbic temporal lobe negative emotionality. The period of adolescence is a neurodevelopmental stage characterized by poor behavioral control as well as strong limbic reward and thrill seeking. Repeated drug abuse and/or stress during this stage increase the risk of addiction and elevate activator innate immune signaling in the brain. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a key glial transcription factor that regulates proinflammatory chemokines, cytokines, oxidases, proteases, and other innate immune genes. Induction of innate brain immune gene expression (e.g., NF-κB) facilitates negative affect, depression-like behaviors, and inhibits hippocampal neurogenesis. In addition, innate immune gene induction alters cortical neurotransmission consistent with loss of behavioral control. Studies with anti-oxidant, anti-inflammatory, and anti-depressant drugs as well as opiate antagonists link persistent innate immune gene expression to key behavioral components of addiction, e.g., negative affect-anxiety and loss of frontal–cortical behavioral control. This review suggests that persistent and progressive changes in innate immune gene expression contribute to the development of addiction. Innate immune genes may represent a novel new target for addiction therapy

Thiamine deficiency-induced neurodegeneration and neurogenesis

Wernicke-Korsakoff syndrome (WKS) is a thiamine deficiency-induced neurodegenerative disorder that culminates in a bilateral diencephalic lesion and severe amnesia. The pyrithiamine-induced thiamine deficiency (PTD) animal paradigm models the neuropathology and behavioral impairments observed in WKS. A hallmark feature of WKS/PTD is hippocampal dysfunction in the absence of anatomical lesion. Extensive literature exists demonstrating a vital role for neurogenesis in hippocampus-based learning and memory function. Thus, a reduction of hippocampal neurogenesis may contribute to the amnestic syndrome associated with WKS and PTD. The current series of experiments sought to determine the consequences of PTD treatment on hippocampal neurogenesis. In the first experiment (Chapter 2), stage-dependent alterations of neurogenesis and gliogenesis were assessed in the hippocampal granule cell layer. Experimental thiamine deficiency increased the proliferation, but not survival, of progenitor cells. In contrast, neurogenesis was reduced and astrocytogenesis was increased during the late post-lesion stage of PTD treatment. The altered hippocampal neurogenesis was accompanied by an increase in undifferentiated cell populations during the post-lesion stages. These data demonstrate that long-term changes to neurogenesis might underlie the hippocampal dysfunction in the PTD model. The second experiment (Chapter 3) sought to determine whether voluntary exercise could ameliorate PTD-induced behavioral deficits and rescue hippocampal neurogenesis. Subjects were exposed to a running or stationary wheel for 14 days and were behaviorally tested on two spatial working memory tasks beginning either 24-hours or 2-weeks following the completion of exercise. Wheel running selectively improved PTD-induced behavioral impairments on the plus-maze spontaneous alternation task at the 2-week time point relative to the stationary PTD subjects. At this time point, exercise also increased the survival of progenitor cells, rescued the diminished neurogenesis, and facilitated cellular activation during behavioral testing. Taken together, these data demonstrate that reduced hippocampal neurogenesis (Chapter 2) might underlie some of the spatial memory impairments associated with PTD treatment and that exercise exposure restores behavioral functionality and rescues hippocampal neurogenesis (Chapter 3). Furthermore, diminished hippocampal neurogenesis may contribute to the amnestic symptoms associated with thiamine deficiency and voluntary exercise may serve as a non-invasive therapeutic approach to alleviate the observed long-term memory impairments