Local norepinephrine depletion and learning-related neuronal activity in cingulate cortex and anterior thalamus of rabbits

Summary Multi-unit neuronal activity was recorded in posterior cingulate cortex (area 29) and the anterior ventral (AV) thalamic nucleus during discriminative instrumental avoidance learning wherein a response (stepping in an activity wheel) to a 0.5-s tone (CS⁺) prevented a foot-shock 5 s after CS⁺ onset. Presentations of a different tone (CS^-) on 50% of the conditioning trials in an irregular sequence with the CS⁺ did not predict shock and thus required no response. Two groups of rabbits received intracranial micro-injections of 6-hydroxydopamine (6-OHDA) to locally deplete the NE in area 29 or the AV nucleus. Vehicle was injected in the non-depleted area in each group and a third group received vehicle injections in both areas. Dopamine neurons in subjects that received 6-OHDA were protected by pre-treatment with GBR-12909. Neuronal data were collected during two pre-training sessions in response to the tones only and when the tones and shock were presented unpaired. Thalamically depleted rabbits made more, and cortically depleted rabbits made fewer, avoidance responses than controls during the early stages of behavioral acquisition, and cortically depleted rabbits made fewer responses than controls and thalamically depleted rabbits during extinction testing administered after the completion of acquisition. One effect of NE depletion on neuronal activity was entirely local: elimination of neuronal sensitization effects (enhanced discharges elicited by tones during the unpaired tone-shock pre-training treatment relative to pre-training with tones only). Other neuronal effects of NE depletion were system-wide, i.e., they occurred whether the depletion was cortical or thalamic. These were: attenuation of area 29 tone-elicited neuronal discharges and enhancement of AV thalamic discharges before and during training; elimination in area 29 of neuronal discrimination between CS⁺ and CS^-, induced in controls by CS⁺-shock pairings in the first conditioning session; induction of this neuronal discrimination, not present in controls, in the AV nucleus during the first conditioning session; attenuation of discharge enhancements elicited in controls by unexpected stimuli (presentation of auditory stimuli different in quality and incidence from the CS⁺). Excepting the noted losses at the outset of training, the results did not support an involvement of NE in the production of cingulate cortical or AV thalamic excitatory and discriminative training-induced neuronal activity. The system-wide alterations due to NE depletion implicated NE in the processing of unexpected events and in the production of dynamic neuronal patterns relevant to mnemonic retrieval. Several of the depletion-related neuronal changes were similar to the effects of hippocampal formation (subicular) lesions, suggesting that NE-dependent functions in area 29 and the AV nucleus are governed by hippocampal efferents, which may control the release of NE in these areas.