The effects of environmental enrichment on memory and synaptic

EE has been shown to enhance learning and memory in various behavioural tasks, such as spatial memory in the Morris water maze (Falkenberg et al., 1992; Kempermann et al., 1997), emotional memory in fear conditioning (Rampon et al., 2000a; Duffy et al., 2001) and recognition memory in novel object recognition task (Rampon et al., 2000a). The enhancement in these forms of learning and memory has been attributed to the structural and biochemical changes described above. It is

81 important to recognise that voluntary exercise in the running wheel in SH conditions has also been shown to enhance spatial learning (van Praag et al., 1999). Therefore it is worth noting that the type of objects/exercises available in the EE condition could affect the outcome observed. This among other variables have been discussed in the literature which can contribute to behavioural as well as biochemical changes seen after EE (Simpson and Kelly, 2011).

Whether EE promotes learning and memory via enhancing hippocampal LTP or LTD is controversial. The controversy has been driven principally by the varying experimental factors, some of which are age, sex, species and duration of EE. These have been highlighted in some studies shown in Table 1.1.

fEPSP LTP

(HFS)

LTD (LFS)

Area Species Sex Age EE

Duration (weeks)

Reference

X Enhanced Enhanced CA1 Rat M P50 5 cont (Artola et

al., 2006)

Enhanced Decreased X DG Rat M P40 4 per (Foster et

al., 1996)

NC NC Decreased CA1 Rat M P28 12 cont (Eckert

and Abraham, 2010)

NC Enhanced X CA1 Mouse F P28 8 cont (Duffy et

al., 2001)

X Enhanced X CA1 Mouse F P21 10 cont (Maggi et

al., 2011)

NC NC X DG Mouse M Adult 2 per (Feng et

al., 2001)

Table 1.1; The range of electrophysiology findings from EE experiments and their variables. This table represents the results for whether after EE, the fEPSP (field excitatory postsynaptic potential), LTP or LTD were enhanced, decreased, had no change (NC) or were not studied (X) from several studies. LTP was induced using high-frequency stimulation (HFS) and LTD was induced using low-frequency stimulation (LFS). The table also contains the area of the hippocampus from which electrophysiological recordings were taken as well as the animal species, sex (m; Male, F; Female) and age at which they were exposed to EE. The duration of EE is also specified in the number of weeks the animals were exposed to EE and whether it was continuous (cont) EE or periodic enrichment (per).[Adapted from (Eckert and Abraham, 2013)].

82 The enhancement in LTP after EE seen in some conditions shown in Table 1.1 could be attributed to several factors. The first is an increase in neurogenesis in the dentate gyrus has been shown to contribute to HFS-induced LTP stimulated in the medial perforant path (Snyder et al., 2001). Therefore the increase in neurogenesis during EE could attribute to changes in plasticity. There are two common hypotheses (1) where EE promotes a learning-induced change in synaptic strength or (2) that EE contributes to a change in long-term plasticity mechanisms such as affecting the ability of neurones to strengthen or weaken their synapses. Changes in synaptic strength can be measured by monitoring basal synaptic transmission (i.e. fEPSP) (Table 1.1). Changes in LTP or LTD can be used to observe changes in plasticity after EE (Table 1.1) (Eckert and Abraham, 2013). If the mechanism for LTP and learning were similar then one would expect that if there were any changes in synaptic strength due to EE then this would occlude subsequent LTP induction i.e. LTP saturation occurs (Moser et al., 1998). On the other hand, an enhancement in LTP/LTD induction or maintenance might be observed in EE animals where plasticity mechanisms have changed due to enriched conditions. Lastly there may be no changes in plasticity post EE that are detectable during LTP or LTD which could be due to the EE protocol where the duration or complexity was not high enough to induce observable changes (Table 1.1).

Not much is known about the EE-dependent molecular signalling pathways involved in synaptic plasticity. However a signalling pathway was suggested when LTP-induced plasticity during EE was compared between adolescent and adult mice (Li et al., 2006a). When a protocol known as theta burst stimulation (TBS) was used to induce LTP in adolescent EE mice, the activation of p38 MAPK and cAMP- dependent signalling was observed. These signalling effectors were unaffected in the SH mice. To further detect a signalling pathway, Ras-GRF1 shown to be involved in NMDA-ERK dependent LTP and Ras-GRF2 known to activate NMDA-p38 dependent LTD were examined using Ras-GRF double KO mice (Li et al., 2006a). TBS-induced LTP in the Ras-GRF double KO mice was defective in adolescent mice but was rescued upon EE. Interestingly this EE-dependent signalling pathway was not observed in adult mice and therefore suggests the presence of multiple signalling cascades (Li et al., 2006b). Taking into account all the highlighted variables during EE it is clear that much is still unknown about the physiological and biochemical mechanisms involved during experience-dependent plasticity. However there are a

83 few key candidates, notably BDNF and signalling cascades, for example MAPK, which could contribute to the structural, biochemical and electrophysiological changes associated with EE.

84