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1.  Acetylcholine facilitates recovery of episodic memory after brain damage 
Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex. This is despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we now show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer’s disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory.
doi:10.1523/JNEUROSCI.2947-12.2012
PMCID: PMC3475489  PMID: 23035090
2.  Cholinergic modulation of a specific memory function of prefrontal cortex 
Nature neuroscience  2011;14(12):1510-1512.
SUMMARY
Deficits in prefrontal cholinergic function are implicated in cognitive impairment in many neuropsychiatric diseases, but acetylcholine’s specific role remains elusive. Rhesus monkeys with selective lesions of cholinergic input to prefrontal cortex were unimpaired in tests of decision-making and episodic memory that require intact prefrontal cortex, but were severely impaired on a spatial working memory task. These observations are consistent with a specific role for prefrontal acetylcholine in working memory.
doi:10.1038/nn.2971
PMCID: PMC3432567  PMID: 22057191
cholinergic; prefrontal; dorsolateral; ventrolateral; orbital; frontal; spatial memory; episodic; decision-making; reward
3.  DIFFUSION-WEIGHTED IMAGING TRACTOGRAPHY-BASED PARCELLATION OF THE HUMAN PARIETAL CORTEX AND COMPARISON WITH HUMAN AND MACAQUE RESTING STATE FUNCTIONAL CONNECTIVITY 
Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.
doi:10.1523/JNEUROSCI.5102-10.2011
PMCID: PMC3091022  PMID: 21411650
AIP; MIP; LIP; VIP; IPL; SPL
4.  Comparing the role of the anterior cingulate cortex and 6-hydroxydopamine nucleus accumbens lesions on operant effort-based decision making 
The European journal of neuroscience  2009;29(8):1678-1691.
Both the anterior cingulate cortex (ACC) and mesolimbic dopamine, particularly in the nucleus accumbens (NAc), have been implicated in allowing an animal to overcome effort constraints to obtain greater benefits. However, their exact contribution to such decisions has, to date, never been directly compared. To investigate this issue we tested rats on an operant effort-related cost–benefit decision-making task where animals selected between two response alternatives, one of which involved investing effort by lever pressing on a high fixed-ratio (FR) schedule to gain high reward [four food pellets (HR)], whereas the other led to a small amount of food on an FR schedule entailing less energetic cost [two food pellets, low reward (LR)]. All animals initially preferred to put in work to gain the HR. Systemic administration of a D2 antagonist caused a significant switch in choices towards the LR option. Similarly, post-operatively, excitotoxic ACC lesions caused a significant bias away from HR choices compared with sham-lesioned animals. There was no slowing in the speed of lever pressing and no correlation between time to complete the FR requirement and choice performance. Unexpectedly, no such alteration in choice allocation was observed in animals following 6-hydroxydopamine NAc lesions. However, these rats were consistently slower to initiate responding when cued to commence each trial and also showed a reduction in food hoarding on a species-typical foraging task. Taken together, this implies that only ACC lesions, and not 6-hydroxydopamine NAc lesions as performed here, cause a bias away from investing effort for greater reward when choosing between competing options.
doi:10.1111/j.1460-9568.2009.06726.x
PMCID: PMC2954046  PMID: 19385990
6-hydroxydopamine; choice behaviour; cost–benefit; dopamine; lesion; rat
5.  ADAPTIVE DECISION MAKING AND VALUE IN THE ANTERIOR CINGULATE CORTEX 
NeuroImage  2007;36(Suppl 2):T142-T154.
Choosing an appropriate response in an uncertain and varying world is central to adaptive behaviour. The frequent activation of the anterior cingulate cortex (ACC) in a diverse range of tasks has lead to intense interest in and debate over its role in the guidance and control of performance. Here, we consider how this issue can be informed by a series of studies considering the ACC's role in more naturalistic situations where there is no single certain correct response and the relationships between choices and their consequences vary. A neuroimaging study of response switching demonstrates that dorsal ACC is not simply concerned with self-generated responses or error monitoring in isolation, but is instead involved in evaluating the outcome of choices, positive or negative, that have been voluntarily chosen. By contrast, an interconnected part of the orbitofrontal cortex is shown to be more active when attending to consequences of actions instructed by the experimenter. This dissociation is explained with reference to the anatomy of these regions in humans as demonstrated by diffusion weighted imaging. Lesions to a corresponding ACC region in monkeys has no effect on animals' ability to detect or immediately correct errors when response contingencies reverse, but renders them unable to sustain appropriate behaviour due to an impairment in the ability to integrate over time their recent history of choices and outcomes. Taken together, this implies a prominent role for the ACC within a distributed network of regions that determine the dynamic value of actions and guide decision making appropriately.
doi:10.1016/j.neuroimage.2007.03.029
PMCID: PMC2954047  PMID: 17499161
6.  Effort-based cost-benefit valuation and the human brain 
In both the wild and the laboratory, animals' preferences for one course of action over another reflect not just reward expectations but also the cost in terms of effort that must be invested in pursuing the course of action. The ventral striatum and dorsal anterior cingulate cortex (ACCd) are implicated in the making of cost-benefit decisions in the rat but there is little information about how effort costs are processed and influence calculations of expected net value in other mammals including the human. We carried out a functional magnetic resonance imaging (fMRI) study to determine whether and where activity in the human brain was available to guide effort-based cost-benefit valuation. Subjects were scanned while they performed a series of effortful actions to obtain secondary reinforcers. At the beginning of each trial, subjects were presented with one of eight different visual cues which they had learned indicated how much effort the course of action would entail and how much reward could be expected at its completion. Cue-locked activity in the ventral striatum and midbrain reflected the net value of the course of action, signaling the expected amount of reward discounted by the amount of effort to be invested. Activity in ACCd also reflected the interaction of both expected reward and effort costs. Posterior orbitofrontal and insular activity, however, only reflected the expected reward magnitude. The ventral striatum and anterior cingulate cortex may be the substrate of effort-based cost-benefit valuation in primates as well as in rats.
doi:10.1523/JNEUROSCI.4515-08.2009
PMCID: PMC2954048  PMID: 19357278
anterior cingulate cortex; striatum; decision making; reward; effort; ventral tegmental area
7.  Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection 
Cerebral Cortex (New York, NY)  2009;20(2):282-293.
To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.
doi:10.1093/cercor/bhp097
PMCID: PMC2803729  PMID: 19447862
acetylcholine; hippocampus; macaque; monkey; temporal lobe

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