Hippocampal regenerative medicine: neurogenic implications for addiction and mental disorders

Abstract

Psychiatric illness is a prevalent and highly debilitating disorder, and more than 50% of the general population in both middle- and high-income countries experience at least one psychiatric disorder at some point in their lives. As we continue to learn how pervasive psychiatric episodes are in society, we must acknowledge that psychiatric disorders are not solely relegated to a small group of predisposed individuals but rather occur in significant portions of all societal groups. Several distinct brain regions have been implicated in neuropsychiatric disease. These brain regions include corticolimbic structures, which regulate executive function and decision making (e.g., the prefrontal cortex), as well as striatal subregions known to control motivated behavior under normal and stressful conditions. Importantly, the corticolimbic neural circuitry includes the hippocampus, a critical brain structure that sends projections to both the cortex and striatum to coordinate learning, memory, and mood. In this review, we will discuss past and recent discoveries of how neurobiological processes in the hippocampus and corticolimbic structures work in concert to control executive function, memory, and mood in the context of mental disorders.

Fig. 1. Adult neurogenic development is distinctly affected by neuropsychiatric disease.

a Adult hippocampal neurogenesis is characterized by the development and maturation of stem cells into granular cell layer neurons in the dentate gyrus, which begin their functional journey as radial glia-like stem cells in the hippocampal subgranular zone (SGZ) and differentiate into multipotent progenitors (types I–III; see main text for details) and then into immature neurons/neuroblasts that eventually commit to a mature granular neuronal cell fate. These mature granular neurons form synapses with existing pyramidal neuronal circuitry to maintain cognitive function throughout life. b Conditions that impair the adult neurogenic process include: (i) actively heavy (binge) and/or chronic drug/alcohol use, (ii) major depression and related disorders, (iii) schizophrenia, and (iv) related psychoses. These aberrant neuropsychiatric conditions, all of which are characterized by significant psychosocial stress, likely induce apoptotic damage (i.e., red circles within cells, indicative of cellular breakdown) and subsequently limit the number of radial glia-like stem cells, multipotent progenitors, immature neurons, and mature granule cells in the hippocampal dentate gyrus. c Notably, several conditions increase or reverse the ability of biological processes to elevate the development and maturation state of adult neurons in the hippocampus. For example, while active intake of drugs of abuse is well known to decrease neurogenic development, paradoxically, (i) abstinence during recovery from drugs induces a rheostatic increase in neurogenic potential in the hippocampus. Surprisingly, during states of reward seeking, for example (ii) as a result of relapse in addiction, heightened adult neurogenesis is also observed, which may be maladaptive (e.g., continued drug seeking vs. seeking alternative behaviors to drug taking). Interestingly, other contributors to the increase in neurogenic potential in the context of neuropsychiatric conditions are (iii) antidepressant medications and potentially, (iv) antipsychotic medications.