The overall goal of this proposal is to determine the importance of adult hippocampal neurogenesis to the recovery process following extended access methamphetamine intake. Research into understanding the neurobiological basis of addiction and relapse has significantly progressed, but to date few treatments are known to reverse the drug-induced neuroplasticity changes that convey vulnerability to relapse. Understanding the neuroplastic changes that underlie the relapse stage of addiction can help generate better treatment options for addiction. One potential mechanism to accelerate brain repair during withdrawal is stimulating the generation of neurons from adult neural stem cells - a process known as adult hippocampal neurogenesis. Neural stem cells persist in the adult hippocampal subgranular zone (SGZ). Adult hippocampal neurogenesis is involved in some aspects of methamphetamine addiction, as reinforcing doses of methamphetamine reduce proliferation, differentiation and neurogenesis of neural stem cells in the SGZ. However, the effects of withdrawal from methamphetamine on these stages of hippocampal neurogenesis are unknown. Furthermore, it is unclear if the process of adult neurogenesis can be stimulated during withdrawal;the types of neurons that can be replaced during withdrawal and their ability to integrate into preexisting circuitry. In the proposed studies, innovative genetic, electrophysiological and immunohistochemical techniques and behavioral models will be used to specifically label, stimulate or inhibit adult-generated neurons in the setting of extended access methamphetamine intake. Using these approaches, we will test our central hypothesis that hippocampal neurogenesis contributes to repair after withdrawal from extended access methamphetamine via neuronal replacement;thus, inhibiting this process will impair recovery and stimulating this process will augment recovery and reduce or prevent relapse. Studies in Aim 1 will characterize the long-term survival and integration of adult-generated neurons after methamphetamine self-administration. Experiments in Aim 2 will determine if adult neurogenesis is critical to the prevention of relapse.
In Aim 3, we will determine whether adult neurogenesis during withdrawal contributes to functional recovery and prevents relapse.
Neural stem cells persist in the hippocampus in the adult mammalian brain. The proposed studies seek to determine whether hippocampal neural stem cells play a role in reducing relapse, assist with repair by replacing cells damaged by brain disorders and promote recovery.
|Mandyam, Chitra D; Somkuwar, Sucharita S; Oliver, Robert J et al. (2018) New Neurons in the Dentate Gyrus Promote Reinstatement of Methamphetamine Seeking. J Exp Neurosci 12:1179069518779625|
|Dutta, Rahul R; Taffe, Michael A; Mandyam, Chitra D (2018) Chronic administration of amphetamines disturbs development of neural progenitor cells in young adult nonhuman primates. Prog Neuropsychopharmacol Biol Psychiatry 85:46-53|
|Takashima, Yoshio; Mandyam, Chitra D (2018) The role of hippocampal adult neurogenesis in methamphetamine addiction. Brain Plast 3:157-168|
|Takashima, Yoshio; Fannon, McKenzie J; Galinato, Melissa H et al. (2018) Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking. Brain Struct Funct 223:2197-2211|
|Galinato, Melissa H; Takashima, Yoshio; Fannon, McKenzie J et al. (2018) Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory. J Neurosci 38:2029-2042|
|Galinato, M H; Lockner, J W; Fannon-Pavlich, M J et al. (2018) A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse. Mol Psychiatry 23:629-638|
|Fannon, McKenzie J; Mysore, Karthik K; Williams, Jefferson et al. (2018) Hippocampal neural progenitor cells play a distinct role in fear memory retrieval in male and female CIE rats. Neuropharmacology 143:239-249|
|Staples, Miranda C; Fannon, McKenzie J; Mysore, Karthik K et al. (2017) Dietary restriction reduces hippocampal neurogenesis and granule cell neuron density without affecting the density of mossy fibers. Brain Res 1663:59-65|
|Somkuwar, Sucharita S; Vendruscolo, Leandro F; Fannon, McKenzie J et al. (2017) Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors. Psychoneuroendocrinology 84:17-31|
|Somkuwar, Sucharita S; Fannon, McKenzie J; Bao Nguyen, Tran et al. (2017) Hyper-oligodendrogenesis at the vascular niche and reduced blood-brain barrier integrity in the prefrontal cortex during protracted abstinence. Neuroscience 362:265-271|
Showing the most recent 10 out of 22 publications