Behavioural Brain Research 203 (2009) 27–34 Contents lists available at ScienceDirect Behavioural Brain Research j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b b r Research report Habituation-induced neural plasticity in the hippocampus and prefrontal cortex mediated by MMP-3 John W. Wright a,b,c,∗ , Peter C. Meighan b,c , Travis E. Brown b,c , Roberta V. Wiediger a , Barbara A. Sorg b,c , Joseph W. Harding a,b,c a Department of Psychology, Washington State University, Pullman, WA 99164-4820, United States b Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164-6520, United States c Program in Neuroscience, Washington State University, Pullman, WA 99164-6520, United States a r t i c l e i n f o Article history: Received 6 May 2008 Received in revised form 9 April 2009 Accepted 13 April 2009 Available online 21 April 2009 Keywords: Habituation Nonassociative learning Head-shake response Spontaneous recovery Matrix metalloproteinases MMP-3 MMP-3 inhibitor Neural plasticity a b s t r a c t Head-shake response (HSR) habituation was presently used to investigate the phenomena of sponta- neous recovery and neural plasticity. Independent groups of rats were presented with five consecutive habituation sessions separated by inter-session intervals (ISIs) of 2, 24 or 72 h. At the conclusion of testing hippocampus and prefrontal cortex tissue samples were collected for determination of matrix metalloproteinase-3 (MMP-3:stromelysin-1) expression as a marker of neural plasticity. The results indi- cated that by the fifth session the 2 h ISI group showed no spontaneous recovery, the 72 h ISI group revealed nearly complete spontaneous recovery; while the 24 h ISI group showed intermediate recovery. MMP-3 expression in the hippocampus and prefrontal cortex was elevated in the 2 and 72 h ISI groups, but not in the 24 h group. A second experiment utilized 7-day osmotic pumps to intracerebroventricu- larly infuse an MMP-3 inhibitor for 6 days. The animals were then tested on the seventh day using the 2 h ISI protocol.Delivery of the MMP-3 inhibitor facilitated spontaneous recovery, thus compromising the animal’s ability to appropriately habituate. This effect was accompanied by a significant inhibition of hippocampus and prefrontal cortex MMP-3 expression. These results suggest that elevations in hip- pocampus and prefrontal cortex MMP-3 expression contribute to this simplest form of learning and may be a mechanism underlying spontaneous recovery. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Habituation is characterized by the gradual waning of a behav- ioral response to repeated stimulation and is considered the simplest form of learning [21,44]. This decrement in response strength cannot be attributed to sensory adaptation or motor fatigue, but is thought to involve neural plasticity within the cen- tral nervous system [8]. Habituation has been documented across many species for several response systems ranging from the gill- withdrawal reflex in Aplysia [9] and tap withdrawal or chemotaxic response in the nematode Caenorhabditis elegans [4,41], to acoustic startle response in rats and mice [37,43] and feeding in humans [13]. The hippocampus (reviewed in [11,23,27,28,38,39]) and prefrontal cortex [49,51] have been implicated in the control of inhibitory processes, particularly habituation, and were the focus of this inves- tigation. ∗ Corresponding author at: Department of Psychology, PO Box 644820, Washing- ton State University, Pullman, WA 99164-4820, United States. Tel.: +1 509 335 2329; fax: +1 509 335 5043. E-mail address: wrightjw@wsu.edu (J.W. Wright). The head-shake response (HSR) consists of a rapid rotation of the head about the anterior to posterior axis in response to a mild air stimulus applied to the ear [2]. This response follows a decreas- ing negatively accelerated function of stimulus frequency such that the higher the rate of stimulus presentation, the faster the rate of habituation. Following habituation the HSR spontaneously recovers as a function of the inter-session interval (ISI),reaching approxi- mately 85–90% of its original response strength following 24 h of rest [33,49]. Our laboratory has utilized altered levels of matrix metallo- proteinases (MMPs) as markers of neural plasticity in an effort to understand the role of these proteinases in the central media- tion of spatial learning and habituation.The MMP family consists of zinc-dependent endopeptidases initially released from neu- rons and glia as inactive zymogens, but become activated once outside the cell (reviewed in [14,42]).MMPs are important con- tributors to the process of neural plasticity because they degrade the extracellular matrix (ECM), thus permitting synaptic restructur- ing (reviewed in [10,12,14,31]). The proteolytic activity of MMPs is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs) designed to inhibit the active forms of MMPs by forming tight non- covalent complexes with them (reviewed in [5,24]). Our laboratory 0166-4328/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2009.04.014