Traumatic brain injury and hippocampal neurogenesis: Functional implications

Abstract

In the adult brain, self-renewing radial-glia like (RGL) progenitor cells have been shown to reside in the subventricular zone and the subgranular zone of the hippocampus. A large body of evidence shows that experiences such as learning, enriched environment and stress can alter proliferation and differentiation of RGL progenitor cells. The progenitor cells present in the subgranular zone of the hippocampus divide to give rise to newborn neurons that migrate to the dentate gyrus where they differentiate into adult granule neurons. These newborn neurons have been found to have a unique role in certain types of hippocampus-dependent learning and memory, including goal-directed behaviors that require pattern separation. Experimental traumatic brain injury (TBI) in rodents has been shown to alter hippocampal neurogenesis, including triggering the acute loss of newborn neurons, as well as progenitor cell hyper-proliferation. In this review, we discuss the role of hippocampal neurogenesis in learning and memory. Furthermore, we review evidence for the molecular mechanisms that contribute to newborn neuron loss, as well as increased progenitor cell proliferation after TBI. Finally, we discuss strategies aimed at enhancing neurogenesis after TBI and their possible therapeutic benefits.

Keywords: Context discrimination; Hippocampus; Pattern separation; Subgranular zone; Traumatic brain injury.

Figure 1.. Differentiation of progenitor cells into mature granule neurons.

The timeline of maturation is indicated above each stage. Each stage of progenitor cell differentiation can be studied using antibodies to the indicated markers. The axons of mature neurons join the mossy fibers where they make synapses with CA3 neurons.

Figure 2.. Examples of cognitive tasks used to assess the role of adult hippocampal neurogenesis.

A) Context fear discrimination task (Frankland et al., 1998; Huckleberry et al., 2016). In this task, a test animal is repeatedly exposed to two chambers that share some features, but are different in others. In the “shock” chamber, the animal receives a mild foot shock in the absence of any salient cues (e.g. tone or light), while no shock is delivered in the “safe” chamber. The ability to differentiate between the “shock” and “safe” chambers is assessed by monitoring the freezing response over the course of training. B) One-trial context fear (Drew et al., 2010). In this task, animals are trained to fear a training chamber in the absence of a salient cue. After a 1-2 minute exploratory period, a single foot shock is delivered. Fear memory is tested by placing the animal back into the training chamber after a delay and monitoring freezing behavior. The specificity of the fear is assessed by measuring freezing behavior in a novel environment. C) Delayed non-match to place (Clelland et al., 2009). This a variant of the radial arm maze task in which animals are trained over a period of days to find a food pellet placed in a randomly chosen arm. All other arms are blocked during training. During the non-matching phase of the task, animals can choose a newly opened arm that is baited, or the original arm, which is not baited.

Figure 3.. Consequences of CCI and FPI on adult hippocampal neurogenesis.

A large body of literature indicates that controlled cortical im pact injury reduces the survival of newborn neurons within 1-3 days of injury. This reduction in DCX-positive neurons (shown in grey) has been observed in rats, mice, and New Zealand rabbits both ipsilateral and contralateral to the injury. Furthermore, CCI also reduces dendritic arborization of the surviving newborn neurons at these acute time points. Concurrent with this loss of newborn neurons, examination of BrdU incorporation (indicated in red) has revealed that enhanced proliferation of neural progenitor cells occurs as early as 24 hrs post-injury. A large percentage of these cells fail to make synaptic connections with CA3 neurons, and undergo apoptosis. Both the surviving newborn neurons (generated prior to injury) and the newly generated neurons (indicated in red color) can mature into granule neurons and incorporate into the hippocampal circuit by 3-6 weeks post-generation. Fluid percussion injury does not appear to cause acute loss of doublecortin-positive cells, but does result in enhanced progenitor cell proliferation. Although generally thought to be a reparative mechanism, enhanced neurogenesis has been reported to potentially reduce the threshold for seizure activity.