Learning Impairment and Cholinergic Deafferentation after Cortical Nerve Growth Factor Deprivation

Abstract

Cholinergic basal forebrain (CBF ) neurons have been shown to respond in vivo to exogenous administration of NGF. Although neurotrophins and their receptors are widely expressed in the CNS, little data exist for the physiological significance of endogenous neurotrophin signaling in CNS neurons. To test directly whether cortically derived NGF is functionally required for the cholinergic functions mediated by the cerebral cortex, repeated injections of anti-NGF mAbs were locally applied into the insular cortex (IC) of rats. The biochemical results, using an in vivo microdialysis technique, showed a dramatic lack of extracellular release of acetylcholine after high potassium stimulation compared with controls. Furthermore, by using small injections of the neurotracer fluorogold, we found a corresponding disruption in the connectivity between the IC and the CBF. Behavioral experiments showed that the NGF antibodies applied into the IC produced a significant disruption on the acquisition of conditioned taste aversion and inhibitory avoidance learning. However, the same animals were able to recall the taste aversion when the conditioning trial was established before injections of NGF antibodies. Given these results, it seems that cortical cholinergic functions are actively dependent on locally derived NGF in the adult normal brain, and that the cholinergic activity from the CBF is not necessary for recalling aversive stimuli, but is necessary for the acquisition of aversively motivated conditionings.

Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories

“…For the CTA acquisition, water in the graded tube was substituted with 0.1% saccharin solution, and 30 min later, when the microdialysis procedure was finished (see below), the animals were injected i.p. with a LiCl (0.4 M, 7.5 ml͞kg) solution to induce digestive malaise (22). For the next 3 days, water baselines were recorded inside the microdialysis chamber, and, on the 10th day, microdialysis was carried out during retrieval (test) of CTA, the water was substituted for 0.1% of saccharin solution to test taste aversion.…”

“…Recently, experiments of NBM lesions have brought a differential role of cholinergic activity during learning and memory. For example, bilateral cortical administration of antibodies for nerve growth factor produced a nearly total loss of cortical ACh levels, and a significant decrement of cells in the NBM, as well as impaired acquisition, but not retrieval, of conditioned taste aversion and inhibitory avoidance (22). However, the role of the cortical ACh release, mediated by NBM afferents, during acquisition and retrieval of taste aversion memory, has not been assessed directly.…”

A structural basis for memory storage in mammals

“…Thus, a physiological role for neurotrophins in memory seems apparent. It would appear that NGF may also be necessary for memory acquisition: infusion of antibodies to NGF into the insular cortex produces signi®cant de®cits in conditioned taste aversion and avoidance learning (Gutierrez et al, 1997). Previous studies suggest neurotrophins mediate memory processes, as well.…”

Comparison of Galantamine and Donepezil for Effects on Nerve Growth Factor, Cholinergic Markers, and Memory Performance in Aged Rats

“…In the immunohistochemistry and ELISA studies, the effects of the AChEIs on NGF and its receptors, as well as the cholinergic markers ChAT and VAChT (i.e., proteins often described as essential for mnemonic processes; Gutierrez et al, 1997;Woolf et al, 2001), were assessed since they are often diminished in aged subjects and those with AD. NGF binding to its high-affinity receptor TrkA causes TrkA dimerization, followed by autophosphorylation of multiple tyrosine residues, which in turn initiates signal transduction events that generally promote the survival of cholinergic neurons.…”