Nerve Growth Factor and Behavioral Recovery After Brain Damage in Rats

Summary

Two prominent features of Alzheimer’s disease are: 1. a marked decrease in forebrain cholinergic markers and 2. a strong impairment in cognitive functions. Since the late 1970s, evidence has accumulated indicating that nerve growth factor (NGF) acts as a neurotrophic factor for cholinergic neurons of the basal forebrain. There are conflicting data concerning the action of this protein on cognitive functions, particularly in animals with lesions affecting forebrain cholinergic systems. NGF has been reported to alleviate lesion-induced as well as aging-related behavioral impairments, but others have reported no NGF effect or even NGF-induced behavioral impairments (e.g., Will et al. 1988; Hefti et al. 1989). The present report attempts to clarify this issue. In a series of experiments conducted on female rats with medial septal lesions, we assessed the short- and long-term effects of a single intrahippocampal injection of NGF made at the time of lesion surgery. Behavior was measured in a test battery including spontaneous alternation and radial maze performance. The results were as follows:

• 1. a single injection of NGF was sufficient to alleviate some behavioral deficits in a long-lasting fashion;

• 2. the beneficial effect of NGF on behavioral recovery was dependent on the size of the septal lesion, since it was observed only in rats with small or medium-sized lesions;

• 3. even if exogenous NGF affected sympathetic sprouting induced by hippocampal cholinergic deafferentation (although this does not seem to be the case), such sprouting did not prevent the protein from facilitating behavioral recovery, and furthermore, superior cervical ganglionectomy did not affect behavioral expression following NGF treatment; and

• 4. when added to cholinergic-rich grafts (embryonic septal cell suspensions injected into the dorsal hippocampus), NGF increased the size of the grafts, especially when given in conjunction with ganglionectomy. These data support other findings showing beneficial effects of NGF treatment and suggest that repeated or chronic treatment may be no more efficient than acute treatment. These findings may also help us to understand some of discrepancies mentioned above.

This research was supported by a grant from I.N.S.E.R.M. (866-019), from the Fondation pour la Recherche Médicale and from the Fondation Simone and Cino Del Duca.