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.
|Somkuwar, Sucharita S; Fannon, McKenzie J; Staples, Miranda C et al. (2016) Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221:4319-4335|
|Sobieraj, Jeffery C; Kim, Airee; Fannon, McKenzie J et al. (2016) Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221:261-76|
|Somkuwar, Sucharita S; Fannon-Pavlich, McKenzie J; Ghofranian, Atoosa et al. (2016) Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex. Brain Behav Immun 58:357-368|
|Somkuwar, Sucharita S; Fannon, McKenzie J; Head, Brian P et al. (2016) Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function. Neuroscience 328:147-56|
|Staples, M C; Somkuwar, S S; Mandyam, C D (2015) Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats. Neuroscience 305:248-56|
|Galinato, M H; Orio, L; Mandyam, C D (2015) Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus. Neuroscience 286:97-108|
|Kim, Airee; Mandyam, Chitra D (2014) Methamphetamine affects cell proliferation in the medial prefrontal cortex: a new niche for toxicity. Pharmacol Biochem Behav 126:90-6|
|Somkuwar, Sucharita S; Staples, Miranda C; Galinato, Melissa H et al. (2014) Role of NG2 expressing cells in addiction: a new approach for an old problem. Front Pharmacol 5:279|