Chronic intracerebroventricular infusion of nerve growth factor improves recognition memory in the rat Amy M. Birch, Áine M. Kelly * Department of Physiology, School of Medicine, Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Dublin 2, Ireland article info Article history: Received 6 June 2013 Received in revised form 25 July 2013 Accepted 29 July 2013 Keywords: Nerve growth factor Learning and memory Dentate gyrus Synaptogenesis Neurogenesis abstract Nerve Growth Factor (NGF) plays pivotal roles in neuronal survival in the adult mammalian brain and may modulate forms of structural and functional plasticity, including neurogenesis. We have shown previously that six weeks of housing in an enriched environment (EE) that did not include access to running wheels resulted in improved recognition memory concomitant with increased NGF expression and neurogenesis in the hippocampus. Here we have attempted to probe a causal link between NGF and the observed enrichment-induced changes in hippocampal function by assessing the effects of six weeks continuous intracerebroventricular (i.c.v.) infusion of NGF on recognition memory and cell proliferation. We report that NGF-infused rats show enhanced recognition memory when compared with vehicle- treated controls. Expression of NGF and its receptor, TrkA, was increased in treated rats, as was expression of the synaptic vesicle protein, synapsin. Finally, we observed an increase in cell proliferation in the dentate gyrus of NGF-treated rats. These data indicate that chronic infusion of NGF can stimulate an improvement in learning and memory that is associated with specific cellular changes in the hip- pocampus, including synaptogenesis and cell proliferation. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Nerve Growth Factor (NGF) is crucial for neuronal survival and growth (Levi-Montalcini and Hamburger, 1951) and also plays a number of roles in mediating plasticity in several regions of the adult brain, including the hippocampus. For example, NGF is involved in maintenance of long-term potentiation (LTP) in dentate gyrus (Kelly et al.,1998) while blockade of hippocampal NGF reduces LTP and impairs spatial memory (Conner et al., 2009). Furthermore, intrahippocampal infusion of NGF has been reported to enhance memory in an inhibitory avoidance task (Walz et al., 2000) while several studies have reported a positive correlation between NGF expression and learning (O’callaghan et al., 2009, Pham et al., 2002). NGF can activate the low-affinity p75 neurotrophin receptor (p75NTR; Lee et al., 2001) but it is believed that its roles in learning and memory are mediated mainly via its activation of the high-af- finity receptor TrkA. p75NTR is a member of the tumour necrosis factor (TNF) family of receptors and binding to p75NTR is associated with the activation of pro-apoptotic pathways (Roux and Barker, 2002). It has been reported that conditional TrkA knockout mice display selective impairments in cognitive function (Sanchez-Ortiz et al., 2012), although it must be noted that there are some reports of intact learning in TrkA knockout mice (Muller et al., 2012). The mechanisms by which NGF may promote plasticity are manifold. Activation of TrkA induces receptor autophosphorylation, recruitment of adaptor proteins and subsequent activation of the MAP kinase, PI3Kinase/AKt and CAMKII signalling pathways, all of which have been implicated in learning and memory (Patapoutian and Reichardt, 2001). NGF can enhance synaptic communication via increased release of glutamate (Knipper et al., 1994b) and enhancement of synaptogenesis (Garofalo et al., 1992) and may thereby underpin some mechanisms of learning and memory. In the context of adult neurogenesis, increasingly investigated as a key mechanism of plasticity, continuous infusion of exogenous NGF has been shown to enhance the survival of new neurons in the granule cell layer of the dentate gyrus and increase activity in hippocampal cholinergic neurons (Frielingsdorf et al., 2007; Knipper et al., 1994a). These studies indicate that NGF may promote learning and memory via its effects on neuronal signalling, neuronal communication and neuronal morphology. We have shown that a six-week period of housing in an enriched environment (but without access to exercise equipment) improves recognition memory in the rat (Birch et al., 2013). As previous data from our lab has shown exercise alone is a potent memory enhancer and link BDNF to these improvements (Griffin et al., 2009, 2011), we sought to assess the role of additional * Corresponding author. Tel.: þ353 18963794. E-mail address: aikelly@tcd.ie (Á.M. Kelly). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2013.07.023 Neuropharmacology 75 (2013) 255e261