However, the EE-induced changes are not merely transcriptional and extend to effects on the proteome [126–128]. The cellular effects of EE, which are presumably

dependent on molecular changes, include enhanced adult neurogenesis [108,129–133] and synaptic plasticity [134–139]. Specific neuronal cell populations have been shown to be activated by EE [140] and the effects in the brain extend to glia [141–143]. However, a range of other cellular effects have been described, including those impacting on metabolism [144], the immune system [145–148] and the HPA-axis [47,149–151]. The EE-induced increase in adult hippocampal neurogenesis may contribute to enhancement of specific cognitive functions, in particular pattern separation [108,152–154], but is unlikely to be PLX-4720 datasheet sufficient for the broader behavioural benefits [155]. One

BIBW2992 in vivo key question that arises from EE studies is the extent to which the different components of EE (sensory stimulation, cognitive activity and physical exercise) can be separated and analysed with respect to their beneficial effects. The easiest aspect to assess separately, and the most studied, has been physical exercise. Laboratory mice and rats will voluntarily run long distances when provided with ad libitum access to running wheels. Whilst other forms of exercise, such as treadmill running have been used, those that require aversive stimuli to induce exercise are known to increase stress, which can confound such experiments. There is evidence that increased voluntary physical exercise (usually wheel

running) can enhance cognition and alter affective and motor states in wild-type rodents, and may induce at least some of the cellular changes associated with EE [5,7,156–158]. One idea which has been previously proposed is that mechanisms mediating the kinds of experience-dependent plasticity discussed above could be investigated for the development of ‘enviromimetics’, drugs which would mimic or enhance EE-induced therapeutic effects [159,160]. Enviromimetics could boost the beneficial effects of cognitive stimulation and physical activity. Physical exercise is known to contribute to many of the major effects of Tenofovir EE, such as increased adult hippocampal neurogenesis [5,156,161–163]. A more specific form of enviromimetic could thus be an ‘exercise mimetic’ that selectively enhances molecular and cellular processes induced by physical activity. So what might be an example of a well characterized molecular target for enviromimetic drugs? The most obvious example is BDNF, a neurotrophin whose expression is found to be induced by increased physical exercise [164], learning [165] and EE [124,125]. Furthermore, BDNF has been implicated in mechanisms of adult neurogenesis and synaptic plasticity, and thus is a key mediator of experience-dependent cellular plasticity in both the developing and adult nervous system [166].