Baxter MG, Kyriazis DA, Croxson PL (2008) Cholinergic depletion of prefrontal cortex impairs acquisition of the delayed response task in rhesus monkeys. Neuroscience 2008 Abstracts 292.9/SS22. Society for Neuroscience, Washington, DC.

Summary: The involvement of corticopetal cholinergic projections in cognition remains difficult to define. Some investigators have suggested that normal cortical function requires an intact cholinergic input, whereas others emphasize a selective role of acetylcholine in attentional function or plasticity. Because of the anatomical and functional homology of human and macaque cortical structures, studies of the effects of selective ablation of cholinergic projections to cortical regions in the macaque would clarify the functions for which these projections are essential. We have tested 3 male rhesus monkeys with multiple bilateral injections of the immunotoxin ME20.4-saporin into lateral and orbital prefrontal cortex on a suite of cognitive tasks dependent on the integrity of orbital and ventrolateral prefrontal cortex, on which they were unimpaired. These tasks included new object-in-place scene learning, strategy implementation, and reinforcer devaluation. To determine the involvement of acetylcholine in dorsolateral prefrontal cortex function, we then trained these monkeys on the spatial delayed response task (Goldman, 1970; Bachevalier and Mishkin, 1986) in a manual testing apparatus. In this task the monkey watches as an experimenter places a small food reward in one of two wells of a test tray and then covers both wells with identical gray plaques. After a brief delay (1-5 sec) during which an opaque screen is interposed between the monkey and experimenter, the monkey is allowed to obtain the reward by displacing the plaque covering the well that was baited by the experimenter. Thus, the monkey must maintain the baited location (left or right) in memory during the brief delay interval in order to choose correctly. Performance of this task is devastated by ablation of dorsolateral prefrontal cortex. The monkeys with cholinergic depletion of lateral and orbital prefrontal cortex were also unable to learn the task to criterion, which four unoperated control monkeys learned readily. This finding suggests that acetylcholine, although not critical for functions of ventrolateral and orbital prefrontal cortex, is essential for dorsolateral prefrontal cortex function. An alternative explanation, which we are currently investigating, is that acetylcholine is necessary for the prefrontal cortex to adapt to the different task demands of delayed response, relative to the tests of discrimination learning with which these monkeys had extensive experience. This would be consistent with a role for cholinergic input to neocortex in cortical plasticity and remodeling.

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Browning PG, Gaffan D, Baxter MG (2007) Severe visual learning impairments in monkeys with combined but not separate lesions of the temporal cortical cholinergic system and the fornix. Neuroscience 2007 Abstracts 341.7. Society for Neuroscience, San Diego, CA.

Summary: A dense amnesia can be produced in the monkey by sectioning the anterior temporal stem, amygdala and fornix, a procedure which deafferents temporal cortex from modulatory inputs from the midbrain and basal forebrain. The present experiment investigated the neurochemical specificity of these severe learning impairments by selectively destroying cholinergic projections to the entire inferior temporal cortex by making multiple injections of the immunotoxin ME20.4-saporin into the inferior temporal cortex bilaterally. Six male macaque monkeys were preoperatively trained to learn new object-in-place discrimination problems each day until they could rapidly learn many such problems within a testing session. The monkeys then underwent surgery and received either injections of immunotoxin (n=3) or injections of saline (n=3). Both groups of monkeys were unimpaired when postoperative and preoperative performance were compared. Each monkey then underwent a second surgery to transect the fornix. After this surgery monkeys who had previously received injections of immunotoxin into temporal cortex showed a severe learning impairment, whereas monkeys who had previously received injections of saline showed a mild impairment. Monkeys with the combined immunotoxin plus fornix lesion were also severely impaired at concurrent object discrimination learning. These results suggest that different neuromodulatory inputs to inferior temporal cortex may act in concert to support cortical plasticity in visual learning such that the loss of acetylcholine only is not sufficient to disrupt normal learning behavior. The results also suggest that in monkeys, as in humans with Alzheimer’s disease, severe memory impairments occur only when a loss of acetylcholine projections to cortex is accompanied by organic tissue damage.

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Baxter MG, Kyriazis DA, Croxson PL (2007) Cholinergic depletion of prefrontal cortex does not impair episodic memory or strategy implementation in rhesus monkeys. Neuroscience 2007 Abstracts 341.9. Society for Neuroscience, San Diego, CA.

Summary: The prefrontal cortex is involved in regulating multiple aspects of memory, decision-making, and cognitive control. Cholinergic input to prefrontal cortex is thought to be involved in supporting its functions. To examine this hypothesis we tested 4 rhesus monkeys (3 male) with cholinergic depletion of ventrolateral prefrontal cortex (N=2) or the entire prefrontal cortex, excluding its medial aspect (N=2). Selective cholinergic depletion was produced by multiple injections of the immunotoxin ME20.4-saporin (0.02 ug/ul) into the prefrontal cortex. These monkeys were tested on two tasks that each require frontal-inferotemporal interaction, as well as an intact ventrolateral prefrontal cortex. The first, strategy implementation, requires monkeys to apply different choice strategies to different categories of objects in order to maximize the rate of reward delivery, and engages decision-making and cognitive control. The second, scene memory, is a test of episodic memory in which monkeys rapidly learn 20 new object-in-place scene discrimination problems within a single test session. Cholinergic depletions of prefrontal cortex, whether they were limited to ventrolateral prefrontal cortex or included the whole of lateral and orbital prefrontal cortex, were without effect on either strategy implementation or new scene learning relative to each monkey’s preoperative performance. Thus, episodic memory and strategy implementation can proceed normally even with severely disrupted cholinergic input, so loss of cholinergic input on its own cannot explain impaired prefrontal function in conditions such as Alzheimer’s disease. Acetylcholine may work in tandem with other neuromodulators to affect prefrontal cortex function; alternatively, it may only be involved in very specific aspects of cortical function, for example representational plasticity.

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Gaffan D, Baxter MG, Browning PGF (2007) Intact delayed nonmatching-to-sample in monkeys with combined lesions of the temporal cortical cholinergic system and the fornix. Neuroscience 2007 Abstracts 341.11. Society for Neuroscience, San Diego, CA.

Summary: Rhesus monkeys were pre-operatively trained in truly trial-unique delayed nonmatching-to-sample (DNMS) in an automated apparatus. They were then divided into a control group (n=3) and an experimental group (n=3) and received injections into the inferior temporal cortex of either saline (controls) or the selective cholinergic immunotoxin ME20.4-saporin (experimentals). A postoperative DNMS test showed no significant impairment in the experimental group, both groups performing at their pre-operative level. Both groups then underwent a second surgery to transect the fornix. Again, there was no significant impairment in DNMS, both groups performing at their pre-operative level. If the lesions are confirmed histologically then these results are in marked contrast to our findings with scene learning, in which monkeys with the same combined lesion as those in the present experimental group were severely impaired. However, a number of recent studies have shown that tasks with temporally complex events extended over trials, like DNMS, discrimination learning set, and serial reversal set, depend on a short-term prospective memory strategy that is supported by the interaction of temporal cortex with prefrontal cortex. Thus, the performance of DNMS does not require the laying down of new long-term memories.

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Schechter LE, Smith DL, Rosenzweig-Lipson S, Sukoff SJ, Dawson LA, Marquis K, Jones D, Piesla M, Andree T, Nawoschik S, Harder JA, Womack MD, Buccafusco J, Terry AV, Hoebel B, Rada P, Kelly M, Abou-Gharbia M, Barrett JE, Childers W (2005) Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. J Pharmacol Exp Ther 314(3):1274-1289. doi: 10.1124/jpet.105.086363

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Kamke MR, Brown M, Irvine DR (2005) Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex. Hear Res 206(1-2):89-106. doi: 10.1016/j.heares.2004.12.014

Summary: In this study the authors assessed the use of a cholinergic immunotoxin while examining cholinergic basal forebrain input to the primary auditory cortex in cat. Six 0.5 µg injections of ME20.4-SAP (Cat. #IT-15) were made into the putamen/globus pallidus, and cholinergic cell survival was examined by immunohistochemistry. The injected area showed a large reduction in number of AChE-positive fibers in the primary auditory cortex. This provides the evidence of the efficacy of ME20.4-SAP for investigating plasticity in cat auditory cortex.

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Wiley RG, Lappi DA (2005) Molecular neurosurgery with targeted toxins. Humana Press, Totowa, New Jersey.

Summary: The idea behind the book was to provide a road map for the users of Molecular Neurosurgery to see how experienced scientists used these exceptional reagents in their work. Experiments with several targeted toxins are described, and readers can get an idea either specifically about a targeted toxin that they’re using, or about how a type of molecule is used and at what dosage, in a paradigm similar to theirs.

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Ridley RM, Baker HF, Leow-Dyke A, Cummings RM (2005) Further analysis of the effects of immunotoxic lesions of the basal nucleus of Meynert reveals substantial impairment on visual discrimination learning in monkeys. Brain Res Bull 65(5):433-442. doi: 10.1016/j.brainresbull.2005.02.025

Summary: Several studies in marmoset monkeys indicate that cholinergic projections from the NBM to specific portions of the neocortex are necessary for visual discrimination learning. By combining analysis of studies using a total of 1.4 µg of ME20.4-SAP (Cat. #IT-15) into various areas of the brain, the authors show that degeneration of cholinergic projections contributes to the loss of functions dependent on the neocortex.

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Dudkin KN, Chueva V, Makarov FN, Bich TG, Roer AE (2005) Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer’s disease. Neurosci Behav Physiol 35(3):281-289. PMID: 15875490

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Turchi J, Saunders RC, Mishkin M (2005) Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys. Proc Natl Acad Sci U S A 102(6):2158-2161. doi: 10.1073/pnas.0409708102

Summary: The rhinal cortex has been shown to play a critical role in recognition memory. The investigators examined the effect of eliminating cholinergic input to the rhinal cortex on the formation of new visual memories in macaques. Animals were given 0.01 µg injections of ME20.4-SAP (Cat. #IT-15) into the perirhinal and entorhinal cortices. The selective cholinergic deafferentation produced a substantial impairment of visual recognition memory, suggesting that cholinergic activation is essential for the formation of new visual memories.

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