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Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 μg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%-84%) and hippocampus (93%), with relative sparing of entorhinalpiriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1-to 4-Hz power, decreases in 20-to 44-Hz power, and decreases in 4-to 8-Hz intraand interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial

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Nerve growth factor (NGF) enhances cholinergic functioning in animals with a compromised cholinergic basal forebrain (CBF). Immunotoxic lesions targeting low-affinity NGF receptor (p75NGF receptor)-bearing CBF neurons provide a selective model for testing the effects of NGF on residual cholinergic neurons. Rats received PBS or the immunotoxin 192IgG-saporin (192Sap) intracerebroventricularly at two doses (1 or 2.7 microg) known to produce different degrees of cholinergic deficit. Seven weeks after lesioning, half of each group received either NGF or cytochrome c intracerebroventricularly for 7 weeks. The two doses of 192Sap produced 50 and 80% depletions of choline acetyltransferase (ChAT) activity in the neocortex and hippocampus. NGF produced the greatest increase in ChAT activity in controls, intermediate in low-lesioned, and smallest in highly lesioned animals. NGF-treated animals showed reduced weight gain, hyper-responsiveness to acoustic stimuli, and decreased inhibitory avoidance. Although general motor behavior was affected by neither 192Sap nor NGF in an open field task, highly lesioned rats took longer to reach the platform during water maze testing. Impaired spatial orientation in finding a hidden platform at the previously acquired position was mitigated by NGF. Hypertrophic changes of residual CBF neurons, Schwann cell hyperplasia, and aberrant axonal sprouting around the medulla were observed in NGF-treated animals only, independent of the preexisting lesion. Our results indicate that NGF has a limited capacity to enhance functioning of residual CBF neurons. More importantly, NGF augmented fear-related behaviors and adverse neuroproliferative changes that may restrict its therapeutic use.

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