Purpose: The effectiveness of embryonic stem cell (eSC) therapy has been explored in many models of neurological disease and several research groups have shown that eSC treatment leads to improved outcomes in pre-clinical models of traumatic brain injury (TBI). Though functional recovery occurs, few surviving eSCs appear to develop neuronal characteristics; instead the majority of the surviving eSC express glial phenotypes. Additionally, researchers have shown that enriching the post-surgical environment of the subject promotes functional recovery following TBI. The purpose of the current project was to determine if post-surgical environmental enrichment (EE) impacts the survival, migration, and integration of eSCs in a rodent model of TBI and if the presence of these cells lead to improved outcomes. Methods: In the current study, the medial frontal cortex (MFC) of rats was injured using a controlled cortical impact (CCI) device. Immediately following injury the rats were placed into either EE or standard environment (SE) housing and then seven days post-injury rats received either murine cortical eSC or media. Behavioral testing consisted of the Morris water maze (MWM), Barnes Maze (BM), and Rotarod tasks (RR). Results: On the MWM task, TBI/eSC/EE animals performed as well as the Sham/SE and Sham/EE groups. The TBI/eSC/SE, TBI/Media/EE, and TBI/Media/SE groups were impaired compared to the controls. By the end of training on the BM there were no differences between the Sham, TBI/Media/EE, and TBI/eSC/EE groups. On the RR task all animals placed in the EE performed equally well and significantly better than their SE housed counterparts. By the end of training on the RR task, the TBI/eSC/EE group performed as well as the sham counterparts, and though not significant they also surpassed the performance of the injured animals that received enrichment or eSC treatment alone. Conclusions: Combing therapeutic strategies with enriching the post-injury environment is likely to be an important addition to determining the efficacy of pre-clinical therapies.

During a critical period in development, spontaneous and evoked retinal activity shape visual pathways in an adaptive fashion. Interestingly, spontaneous activity is sufficient for spatial refinement of visual receptive fields in superior colliculus (SC) and visual cortex (V1), but early visual experience is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al. 2005(Carrasco et al. , 2011Carrasco & Pallas 2006;Balmer & Pallas 2015a). In visual cortex (V1), brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB are important for development of visual acuity, inhibition, and regulation of the critical period for ocular dominance plasticity (Hanover et al., 1999;Huang et al., 1999;Gianfranceschi et al., 2003). To examine the generality of this signaling pathway for visual system plasticity, the present study examined the role of TrkB signaling during the critical period for RF refinement in SC. Activating TrkB receptors during the critical period (P33-40) in DR subjects produced normally refined RFs, and blocking TrkB receptors in light-exposed animals resulted in enlarged adult RFs like those in DR animals.We also report here that deprivation-or TrkB blockade-induced RF enlargement in adulthood impaired fear responses to looming overhead stimuli, and negatively impacted visual acuity. Thus, early TrkB activation is both necessary and sufficient to maintain visual RF refinement, robust looming responses, and visual acuity in adulthood. These findings suggest a common signaling pathway exists for the maturation of inhibition between V1 and SC. Significance StatementReceptive field refinement in superior colliculus (SC) differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather spontaneous activity is sufficient. Maintenance of refinement beyond puberty requires a brief, early exposure to light in order to stabilize the lateral inhibition that shapes receptive fields. We find that 3 TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, as in some other types of plasticity, TrkB signaling plays a crucial role in RF refinement.

During a critical period in development, spontaneous and evoked retinal activity shape visual pathways in an adaptive fashion. Interestingly, spontaneous activity is sufficient for spatial refinement of visual receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1), but early visual experience is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al., 2005, 2011; Carrasco and Pallas, 2006; Balmer and Pallas, 2015a). In V1, BDNF and its high-affinity receptor TrkB are important for development of visual acuity, inhibition, and regulation of the critical period for ocular dominance plasticity (Hanover et al., 1999; Huang et al., 1999; Gianfranceschi et al., 2003).To examine the generality of this signaling pathway for visual system plasticity, the present study examined the role of TrkB signaling during the critical period for RF refinement in SC. Activating TrkB receptors during the critical period (P33-P40) in dark reared subjects produced normally refined RFs, and blocking TrkB receptors in light-exposed animals resulted in enlarged adult RFs like those in dark reared animals. We also report here that deprivation-or TrkB blockade-induced RF enlargement in adulthood impaired fear responses to looming overhead stimuli and negatively impacted visual acuity. Thus, early TrkB activation is both necessary and sufficient to maintain visual RF refinement, robust looming responses, and visual acuity in adulthood. These findings suggest a common signaling pathway exists for the maturation of inhibition between V1 and SC.Receptive field refinement in superior colliculus differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather, spontaneous activity is sufficient. Maintenance of refinement beyond puberty requires a brief, early exposure to light to stabilize the lateral inhibition that shapes receptive fields. We find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, as in some other types of plasticity, TrkB signaling plays a crucial role in receptive field refinement.

No abstract

Refinement of developing visual projections is reported to depend on visual experience in rats, cats, ferrets, and monkeys. Visual deprivation in these species delays visual pathway development, reportedly maintaining a juvenile condition and prolonging the critical period for plasticity. Deprivation has been associated with retention of immature NMDA and GABAA receptors and a juvenile state of chloride transporters. In contrast, receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1) of Syrian hamsters refine normally with spontaneous activity alone, requiring visual experience only to maintain refined RFs in adulthood. Continued visual deprivation into adulthood leads to RF enlargement. This failure to maintain refined RFs and thus preserve high acuity vision in visually deprived adult SC is associated with a loss of GABA and GAD, caused at least in part by a reduction in BDNF-TrkB signaling. In order to explore the postsynaptic mechanism, we examined GABAA receptor expression levels, location, and subunit composition using Western blotting. In addition, we assayed the GABAA receptor anchoring protein gephyrin and expression levels of the chloride transporters KCC2 and NKCC2. To test the alternate hypothesis that RFs enlarge in adulthood as a result of immature postsynaptic NMDA receptors, we examined NR2A/2B ratios and levels of the anchoring protein PSD-95. We found no evidence supporting visual deprivation-related postsynaptic alterations in receptors, chloride transporters, or anchoring proteins in adult hamsters. Thus, we argue that visual deprivation continued past puberty reveals a new form of maladaptive, inhibitory plasticity in which, rather than retaining juvenile features and extending the critical period, continued lack of inhibition in adulthood reopens the critical period, reversing the refinement of receptive fields to the detriment of visual acuity. These results suggest that attempts to increase plasticity in adulthood for purposes of rehabilitation or recovery from injury should consider the possibility of unintended negative consequences.