SELECTIVE IMMUNOLESIONING OF THE BASAL FOREBRAIN CHOLINERGIC SYSTEM DISRUPTS SHORT-TERM-MEMORY IN RATS

Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic nuclei by the immunotoxin 192 IgG-sap orin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the presen t study, we have tested the effects of 192 IgG-saporin in an operant d elayed matching-to-position task which has previously been used to dis criminate between delay-dependent learning impairments and delay-indep endent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injection s of 5 mu g of 192 IgG-saporin 4 weeks prior to a second testing sessi on. Rats with 192 IgG-saporin lesions displayed a significant delay-de pendent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic bloc ker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and i nduced further impairment also in animals with 192 IgG-saporin lesions . These effects were not observed following control injections of meth yl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvemen t in performance was observed in either group following systemic treat ment with the muscarinic cholinergic agonist arecoline (1.0 mg/kg). Bi ochemical and morphological analyses confirmed the selective and sever e (>90-95%) depletion of cholinergic neurons throughout the septal-dia gonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to p roduce additional damage to the cerebellar Purkinje cells, no gross mo tor abnormalities were observed that could contribute to the effects o n accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-las ting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.