Invited reviewEnvironmental enrichment, alone or in combination with various pharmacotherapies, confers marked benefits after traumatic brain injury
Introduction
Traumatic brain injury (TBI) affects two million people in the United States (Faul et al., 2010) and approximately ten million worldwide each year (Hyder et al., 2007). Moreover, in any given year, 5.3 million Americans live with substantial TBI-related neurobehavioral and cognitive dysfunction (Binder, 1986; Sosin et al., 1996; Draper and Ponsford, 2008; Na et al., 2014). TBI can also lead to psychiatric comorbidities, such as major depression and post-traumatic stress disorder (Rogers and Read, 2007; Ponsford et al., 2012; Warren et al., 2015; Alway et al., 2016; Scholten et al., 2016) that further exacerbate life quality for those afflicted as well as that of family and friends. Numerous events can cause a TBI, but motor vehicle accidents, falls, firearms, and participation in high impact sports are the most common. The economic cost to society, which includes medical care, rehabilitation, and the loss of productivity, is estimated at over $75 billion each year (Max et al., 1991; Selassie et al., 2008).
To curtail this significant health care issue, a plethora of research has been conducted evaluating numerous potential therapies to protect against TBI-induced deleterious effects and/or to promote cognitive and/or motor recovery. Although many pharmacological agents have exhibited robust benefits in the laboratory (for excellent reviews see Kokiko and Hamm, 2007; Wheaton et al., 2009; Bondi et al., 2015a,b; Kline et al., 2016), successful translation to the clinic has been limited (Doppenberg et al., 2004; Beauchamp et al., 2008; Menon, 2009; Menon and Zahed, 2009). Numerous possibilities exist regarding the lack of translation from the bedside to the clinic, but one of the more salient is that single therapies are not adequate to promote recovery from an injury that is multifaceted (Margulies et al., 2009; Kline et al., 2016). A potentially advantageous strategy is to use more than one therapy so that complementary mechanisms of action can target more than one TBI-induced pathophysiology. Additionally, neurorehabilitation should be paramount in the equation as it is currently the only real hope for TBI patients to recover some degree of function and appreciate some independence.
Unlike standard (STD) housing, where rodents are typically paired in traditional shoebox laboratory cages with only food and water, the typical environmental enrichment (EE) paradigm consists of an expansive communal living space that encourages social interaction, physical exercise that is accrued via social play and cage exploration, and engagement with novel objects of various shapes, textures, and sizes that are changed frequently to stimulate sensory perception and cognition (Hamm et al., 1996; Kline et al., 2007b, 2010, 2012; Hoffman et al., 2008b; Sozda et al., 2010; de Witt et al., 2011; Matter et al., 2011; Cheng et al., 2012; Monaco et al., 2013; Pang and Hannan, 2013; Hannan, 2014; Bondi et al., 2014, 2015a,b). The complex interaction of social, motor, and sensory components is essential to achieve the most favorable effects after TBI as demonstrated by Sozda et al. (2010) who manipulated the EE (i.e., omitted one of the components from each of the three resulting conditions) and found that albeit all atypical EE paradigms lead to some functional improvement, only the typical model afforded optimal recovery. Similar outcomes were noted after middle cerebral artery occlusion where the EE model that included all components lead to better functional outcome (Johansson and Ohlsson, 1996; Risedal et al., 2002). Furthermore, EE conditions that exclude components that stimulate physical activity, such as ladders, but that enhance sensory stimulation (i.e., whisker stimulation) limit motor recovery and boost sensory function (Alwis et al., 2016).
EE has been shown for decades to produce plasticity and behavioral improvements in normal (i.e., non-injured) rodents as noted in seminal work by Bennett and colleagues who showed that EE-housed rats developed thicker and heavier cerebral cortices relative to their STD-housed cohorts (Bennett et al., 1964). Similar increases in EE-induced cortical thickening was demonstrated by Diamond and colleagues, who showed that the plastic changes resulted from an increase in the number and length of glia (Diamond et al., 1966). Over the years, EE has been shown to promote larger synapses and higher densities of synaptic vesicles (Nakamura et al., 1999; Nilsson et al., 1999) and to increase neurogenesis in rodents (Kempermann et al., 1997, 1998). EE also increases the pre-and post-synaptic plasticity markers synaptophysin and postsynaptic density protein-95, respectively, in various brain regions (Nithianantharajah et al., 2004). These neural alterations may explain, at least in part, the EE-mediated functional enhancements observed in normal rats. A summary of potential mechanisms following TBI is presented after a discussion of the reviewed manuscripts.
EE has consistently been shown to confer motor, cognitive, and histological benefits after TBI. Moreover, the benefits are observed in both sexes and across the age span in rodents (Bondi et al., 2014, 2015a,b). The efficacy of EE has also been reported after experimental spinal cord injury (Berrocal et al., 2007; Fischer and Peduzzi, 2007; Koopmans et al., 2012; Vachon et al., 2013), Alzheimer's disease (Jankowsky et al., 2005; Cracchiolo et al., 2007; Dong et al., 2012; Stuart et al., 2017), Parkinson's disease (Bezard et al., 2003; Faherty et al., 2005; Jadavji et al., 2006; Jungling et al., 2017), and stroke (Nygren and Wieloch, 2005; Buchhold et al., 2007; Zai et al., 2011; Yu et al., 2013; Kuptsova et al., 2015). EE has traditionally been implemented immediately after TBI and provided continuously until the completion of all behavioral manipulations (Bondi et al., 2014, 2015a,b). However, the conventional model does not resemble the clinical scenario in terms of timing, which limits its translatability. Therefore, our laboratory has focused on methodically advancing the paradigm to make it more clinically relevant by investigating not only the temporal window of when delayed EE implementation may still be effective, but also the quantitative issue of how much enrichment is required to confer benefits. The data suggest that continuous EE can be delayed for at least a week after TBI and still provide significant cognitive enhancement relative to STD controls (Hoffman et al., 2008b; Matter et al., 2011). Furthermore, the benefits are similar regardless of whether EE is provided continually, as in the typical paradigm (Kline et al., 2007b, 2010, 2012; Bondi et al., 2014, 2015a,b), or when administered for only six hours per day (de Witt et al., 2011; Radabaugh et al., 2016). Providing EE in two daily sessions of 3 h rather than a single 6-h session did not yield greater benefits as hypothesized (Radabaugh et al., 2017), but because both time frames were equally beneficial, one clinically important conclusion that can be made is that shorter bouts of rehabilitation may be a practicable option for TBI patients who are unable or unwilling to maximize effort due to TBI-induced fatigue (Minderhoud et al., 1980; Keshaven et al., 1981; LaChapelle and Finlayson, 1998). These findings lend further support for EE as a preclinical model of neurorehabilitation as the experimental design is reminiscent of the clinical scenario where rehabilitation usually does not commence until after the CNS injured patients have been released from neuro-critical care. Moreover, once in rehabilitation, the amount of therapy may be quite limited as indicated by several clinical studies reporting that rehabilitation is provided for only a few hours per day (Blackerby, 1990; Shiel et al., 2001; Zhu et al., 2007). Additional studies supporting EE as a viable preclinical model have shown that the conferred benefits persist for up to six months after cessation of enrichment (Cheng et al., 2012).
Taken together, the studies examining typical, delayed, or abbreviated EE suggest that this rehabilitative paradigm could be instrumental in evaluating potentially effective therapeutic strategies in a combination treatment approach that may subsequently translate to the clinic. Indeed, despite the belief that combining therapies may be more beneficial than single treatments, combination therapies examining the potentially additive and/or synergistic effects of EE and pharmacotherapies have historically been limited. However, in the first comprehensive review of combination treatments after TBI, which focused not only on pharmacotherapies, but also neurotrophic factors and stem cells, Kline and colleagues asked the question “is more better” and based on the literature found the answer to be yes. This was particularly true for those studies that included EE as one of the treatments (Kline et al., 2016). A more recent review by Malá and Rasmussen (2017) reached a similar conclusion regarding the efficacy of EE. To this end, the following sections will discuss combination treatment paradigms that utilized EE and pharmacotherapies after experimental TBI.
To ascertain the relevant studies for inclusion in this review, which focuses on studies of TBI that have utilized EE plus any pharmacotherapy, three different PubMed searches were conducted in December 2017. The first utilized the broad key phrase “combination AND therapy AND traumatic AND brain AND injury” that yielded 622 papers, of which only 3 were relevant. The second included a more restrictive search with the key words “environmental AND enrichment AND brain AND injury AND treatment, which returned 101 possibilities and only 7 that fit the review criteria. The third search was more focused “environment enrichment AND drug AND traumatic brain injury” and produced 15 hits, of which only 7 were relevant. After correcting for overlapping hits among the searches, 9 papers emerged and derive from our laboratories. A review of the bibliographies in the 9 articles did not yield additional citations.
Regarding specifics of all 9 studies and to minimize repetition when discussing each, it should be noted that motor function refers to beam-balance and beam-walking unless otherwise specified, and cognitive performance refers to spatial learning and memory in the Morris water maze (MWM). Moreover, all TBIs were produced via a controlled cortical impact (CCI) of moderate severity (2.8 mm tissue deformation at 4 m/s) and treatment groups were compared to STD-housed controls (vs. EE) and or vehicle (vs. pharmacotherapies). All treatments were administered intraperitoneally. See Table 1 for specifics.
Section snippets
Pharmacotherapies plus EE
Numerous pharmacological agents targeting various neurotransmitter systems in preclinical models of TBI have been reported to enhance functional outcome when provided as single therapies (Kokiko and Hamm, 2007; Wheaton et al., 2009; Bales et al., 2009; Garcia et al., 2011; Cheng et al., 2016). Here, we discuss the results from combination treatment studies where pharmacotherapies were coupled with EE to provide a neurorehabilitation approach that could potentially augment the benefits of each
Potential mechanisms for the therapeutic effects conferred by EE and 5-HT1A receptor agonists after TBI
Numerous brain changes have been reported following EE in normal uninjured animals (Bennett et al., 1964; Diamond et al., 1966; Kempermann et al., 1997, 1998; Nakamura et al., 1999; Nilsson et al., 1999; Nithianantharajah et al., 2004), but as for potential mechanisms for the EE-induced behavioral benefits after TBI, there are only a few studies that have investigated this avenue. Of those that do exist, plasticity and neuroinflammation are the two potential mechanisms evaluated. Prevalent
Summary
Perhaps the most salient conclusion that can be derived from the studies discussed is that EE confers robust motor, cognitive, and histological improvement in male and female as well as adult and pediatric rats after TBI. In a couple of instances, particularly when donepezil and haloperidol were provided concomitantly with EE, the efficacy of this rehabilitative paradigm was attenuated. However, EE was also able to reduce the deleterious effects of these agents on functional recovery after TBI.
Acknowledgements
This work was supported, in part, by NIH grants HD069620, HD069620-S1, NS060005, NS084967 (AEK), NS094950, NS099683 (COB), the University of Pittsburgh Physicians /UPMC Academic Foundation, and the UMPC Rehabilitation Institute (COB).
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