Do new neurons contribute to functional reorganization after brain damage?

The finding that adult neurogenesis occurs constitutively in the brain was a breakthrough in neuroscience and soon gained attention as a possible mechanism for neurorepair after brain damage. In a recent study we show that the dentate gyrus (DG) reorganizes anatomically over time after damage, while new neurons undergo maturation and activate in response to a contextual fear memory recall (Aguilar-Arredondo and Zepeda, 2018). These findings provide new evidence on the possible role of neurogenesis in cognitive recovery after brain injury. The potential of the brain to change continuously, in particular as a consequence of damage, is a focus of attention for neurobiologists. Pioneer studies in the 1980’s first showed that cortical representations were not fixed. Furthermore, it was shown that functional deficits triggered by cortical lesions could be resolved over time resulting in functional reorganization. These observations built on the idea that the brain was plastic, meaning that neuronal cells could change their properties after suffering damage, providing a mean for neurorepair. Nowadays, it has been well established that after damage, surviving neurons modify the balance in its excitatory/inhibitory communication and also undergo axonal and dendritic sprouting, both of which have been suggested to contribute to reorganization. Also, the release of molecules such as trophic factors as well as revascularization and activation of a number of signalling pathways have been shown to contribute to reorganization ultimately facilitating the recovery of functions (for a review, see Wieloch and Nikolich, 2006). In terms of neurorepair, the above-mentioned mechanisms were the main considered to underlie functional recovery until the late 1990s and beginning of the 2000, when a new form of constitutive brain plasticity became widely accepted to occur: adult neurogenesis. For some time, adult neurogenesis in mammals was not a topic of study, in part because of the experimental constrains that posed working with autoradiography, the standard technique used to analyse cell proliferation. The use of the analogue of thymidine BrdU to label new cells via immunohistochemistry together with the use of retroviral particles and the use of conditional animals opened the possibility to study adult neurogenesis for many labs. Since then, several important questions have emerged in relation to the potential functions of new neurons and the associated mechanisms that regulate their production and integration into pre-established neuronal networks. The evidence in mice and more recently in humans showing that different types of brain damage trigger an exacerbated neurogenic response in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus and the subventricular zone (SVZ) at the walls of the lateral ventricles raised the hypothesis that new neurons born in response to damage contributed to the structural and functional reorganization of the brain (Liu et al., 1998; Arvidsson et al., 2002; Jin et al., 2006). Since then, different research groups have evaluated if new cells born in response to damage: 1) survive and achieve maturation; 2) migrate towards the area of lesion; 3) show anatomical integration (i.e., by establishing axonal connections with the target region); 4) show synaptic integration and; 5) display synaptic activation. Ultimately, behavioural studies have aimed at providing a causal link between neurogenesis and functional recovery. In a recent work we show that after a focal lesion to the DG, new neurons born in response to damage survive for at least 30 days and activate in response to a DG-mediated cognitive demand, but not in response to a DG-independent task (Aguilar-Arredondo and Zepeda, 2018). Activation of new neurons occurred in response to retrieval of a contextual fear memory, but not in response to spatial exploration. Along activation, long-term potentiation, which is impaired at 10 days after damage, recovers by 30 days post-injury (Zepeda et al., 2013). The finding that new neurons born after damage become mature while specifically activating in response to contextual fear retrieval, suggests that they achieve to incorporate synaptically into the DG circuit and support the recovery of a cognitive function. Up to now, there is experimental evidence showing that new neurons are produced from 1 and until 16 weeks after middle cerebral artery occlusion showing that continuous SVZ exacerbated neurogenesis after damage is not acute nor transient (Thored et al., 2006). Beyond survival, it has also been shown that new neurons in the DG achieve maturation and send axonal projections to CA3 as evidenced from fluorogold tracing studies (Sun et al., 2007). Neurons born after cortical injury develop electrophysiological properties similar to those of neurons born under physiological conditions and respond to electrical stimulation of their efferent pathway (Villasana et al., 2015) which suggests their potential to integrate functionally into a given neuronal circuit possibly facilitating the reorganization of a damaged neuronal network. Contrary to the hypothesis of functional integration of new neurons in the above-mentioned work, the authors highlight that new neurons born after damage develop but maintain an aberrant morphology. Our results also show that at an early stage after damage, new neurons display an aberrant morphology. But that at later time points the gross morphology of new neurons resembles that of neurons born under control conditions (Aguilar-Arredondo and Zepeda, 2018). These observations are also supported by recent experiments form our lab showing that after damage to the DG, newly-born neurons develop a regular morphology and send their projections to CA3 (unpublished) (Figure 1). These results suggest