Post-stroke Neurogenesis: Friend or Foe?

Abstract

The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell-cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase.

Keywords: SGZ; SVZ; aberrant; adult neurogenesis; cognitive impairment; hippocampus; stroke.

FIGURE 1

Schematic illustration of most representative aberrant dendritic morphology of newborn neurons generated in the DG after stroke. (A) Morphology of regular (“non-aberrant”) neurons. (B) Neurons with additional basal dendrites toward the hilus (bipolar cells) and an increase in dendritic complexity (Niv et al., 2012; Woitke et al., 2017). (C) Neurons with abnormal basal dendrites directed toward the hilus (Niv et al., 2012; Woitke et al., 2017). (D–F) Neurons with a dramatic reduction in apical dendrite length and an increased proximal dendritic branch density (Cuartero et al., 2019; Sheu et al., 2019). (G) Ectopic neurons (Niv et al., 2012; Woitke et al., 2017).

FIGURE 2

Functional consequences of modulation of post-stroke neurogenesis after stroke. (A) The hippocampus is one of the main adult brain regions implicated in cognitive functions. Through adult neurogenesis, newborn neurons are continually added to the hippocampal circuits, contributing to the encoding of new hippocampus-dependent memories. (B) Stroke-induced neurogenesis in the SGZ positively correlates with memory impairment after cerebral ischemia. (C) Enhancement of post-stroke neurogenesis, for instance, by running, exacerbates hippocampal cognitive deficits after ischemia. (D) Post-stroke memory impairment is reduced by abolishment of ischemia-induced aberrant neurogenesis (Cuartero et al., 2019).