Both norepinephrine and acetylcholine have been shown to be critically involved in mediating attention but there remains debate about whether they serve similar or unique functions. Much of what is known about the role of these neurochemicals in cognition is based on manipulations done at the level of the cell body but these findings are difficult to reconcile with data regarding the unique contribution of cortical subregions, e.g. the dorsolateral prefrontal cortex, to attention. In the current study, we directly compared the effects of noradrenergic and cholinergic deafferentation of the rat medial prefrontal cortex, the homologue of primate dorsolateral prefrontal cortex, using an intradimensional/extradimensional attentional set shifting task, a task previously shown to be able to dissociate the function of the primate dorsolateral prefrontal cortex from orbitofrontal cortex. We found that noradrenergic, but not cholinergic, deafferentation produces specific impairments in the ability to shift attentional set. We also clarified the nature of the attentional deficits by assessing the ability of rats to disregard irrelevant stimuli. Noradrenergic lesions did not alter the ability of rats to ignore irrelevant stimuli, suggesting that the attentional deficit results from an overly focused attentional state that retards learning that a new stimulus dimension predicts reward. KeywordsDBH saporin; 192 IgG saporin; infralimbic/prelimbic cortices; selective attention Studies aimed at understanding the neurochemical basis of attention have found that both norepinephrine (NE) and acetylcholine (ACh) mediate aspects of attention (McGaughy and Sarter, 1995b;McGaughy et al., 1996;Rajkowski et al., 2004;Milstein et al., 2007) but some conditions dissociate the functions of these systems. Yu and Dayan (2005) hypothesize that NE mediates unexpected uncertainty while ACh mediates expected uncertainty. In other words, there exists some known ambiguity in many attentional situations, e.g. spatial or temporal unpredictability of targets, and variability in perceptual attributes of target (Chiba et al., 1995;McGaughy and Sarter, 1995a;Bucci et al., 1998;McGaughy et al., 2002;Maddux et al., 2007). After acquisition, this uncertainty though not predictable is known, expected, and requires ACh Dayan, 2002, 2005). Additionally, unexpected uncertain events may occur, e.g. changes in reinforcement contingencies in a well-learned task, and recruit NE (Robbins, 2000;Dalley et al., 2001; Sara, 2004, 2005;Dalley et al., 2004;Yu and Dayan, 2005 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThough these frameworks are useful there remains ambiguity about the attentional situations that require ACh and those that require NE. This ambiguity may result from a reliance on data obtained from manipulations of the cell bodies of these systems (Aston-Jones et al., 1994, 2000McGaughy et al., 1996McGaughy et al., , 2002. Both NE and ACh innervate much of the neocortical mantle so previous frameworks posited a unita...

The current study used fMRI in humans to examine goal-directed navigation in an open field environment. We designed a task that required participants to encode survey-level spatial information and subsequently navigate to a goal location in either first person, third person, or survey perspectives. Critically, no distinguishing landmarks or goal location markers were present in the environment, thereby requiring participants to rely on path integration mechanisms for successful navigation. We focused our analysis on mechanisms related to navigation and mechanisms tracking linear distance to the goal location. Successful navigation required translation of encoded survey-level map information for orientation and implementation of a planned route to the goal. Our results demonstrate that successful first and third person navigation trials recruited the anterior hippocampus more than trials when the goal location was not successfully reached. When examining only successful trials, the retrosplenial and posterior parietal cortices were recruited for goal-directed navigation in both first person and third person perspectives. Unique to first person perspective navigation, the hippocampus was recruited to path integrate self-motion cues with location computations toward the goal location. Last, our results demonstrate that the hippocampus supports goal-directed navigation by actively tracking proximity to the goal throughout navigation. When using path integration mechanisms in first person and third person perspective navigation, the posterior hippocampus was more strongly recruited as participants approach the goal. These findings provide critical insight into the neural mechanisms by which we are able to use map-level representations of our environment to reach our navigational goals.

Groundbreaking research in animals has demonstrated that the hippocampus contains neurons that distinguish between overlapping navigational trajectories. These hippocampal neurons respond selectively to the context of specific episodes despite interference from overlapping memory representations. The present study used functional magnetic resonance imaging in humans to examine the role of the hippocampus and related structures when participants need to retrieve contextual information to navigate well learned spatial sequences that share common elements. Participants were trained outside the scanner to navigate through 12 virtual mazes from a ground-level first-person perspective. Six of the 12 mazes shared overlapping components. Overlapping mazes began and ended at distinct locations, but converged in the middle to share some hallways with another maze. Non-overlapping mazes did not share any hallways with any other maze. Successful navigation through the overlapping hallways required the retrieval of contextual information relevant to the current navigational episode. Results revealed greater activation during the successful navigation of the overlapping mazes compared with the non-overlapping mazes in regions typically associated with spatial and episodic memory, including the hippocampus, parahippocampal cortex, and orbitofrontal cortex. When combined with previous research, the current findings suggest that an anatomically integrated system including the hippocampus, parahippocampal cortex, and orbitofrontal cortex is critical for the contextually dependent retrieval of well learned overlapping navigational routes.

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Observations of temporally graded retrograde amnesia after hippocampal damage suggest that the hippocampal region plays a critical, time-limited role in memory consolidation. However, these observations do not indicate where permanent memory is stored, nor do they clarify whether the hippocampus normally remains involved in a nonessential way. Evidence from multiple neural imaging studies indicate the time-limited role of the hippocampus and suggest that the anterior cingulate cortex is a critical storage site of different types of long-term memory. However, each of the previous studies examined spatial memory, leaving open the question of whether different cortical areas support long-term memory for other types of material. We characterized the course of involvement of cortical and hippocampal areas in animals trained in an explicitly nonspatial task. First, we confirmed previous findings that hippocampal damage produces temporally graded retrograde amnesia for the social transmission of a food preference (STFP) within our experimental protocol. Damage to the hippocampal region 1 d, but not 21 d, after training impaired subsequent recall of STFP. Then, we characterized the anatomical patterns of activation of the immediate early gene c-fos during retrieval of STFP immediately and 1, 2, and 21 d after training. The ventral subiculum was activated during retrieval shortly after learning, but the level of activation declined at successive times. In contrast, olfactory recipient regions including piriform, entorhinal, and orbitofrontal cortex showed the opposite pattern, increasingly greater activation in successively later retrieval tests. These findings support the view that different cortical networks support long-term memory for different types of information.

Parkinson's disease (PD) is largely attributed to disruptions in the nigrostriatal dopamine system. These neurodegenerative changes may also have a more global effect on intrinsic brain organization at the cortical level. Functional brain connectivity between neurocognitive systems related to cognitive processing is critical for effective neural communication, and is disrupted across neurological disorders. Three core neurocognitive networks have been established as playing a critical role in the pathophysiology of many neurological disorders: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). In healthy adults, DMN–CEN interactions are anti-correlated while SN–CEN interactions are strongly positively correlated even at rest, when individuals are not engaging in any task. These intrinsic between-network interactions at rest are necessary for efficient suppression of the DMN and activation of the CEN during a range of cognitive tasks. To identify whether these network interactions are disrupted in individuals with PD, we used resting state functional magnetic resonance imaging (rsfMRI) to compare between-network connectivity between 24 PD participants and 20 age-matched controls (MC). In comparison to the MC, individuals with PD showed significantly less SN–CEN coupling and greater DMN–CEN coupling during rest. Disease severity, an index of striatal dysfunction, was related to reduced functional coupling between the striatum and SN. These results demonstrate that individuals with PD have a dysfunctional pattern of interaction between core neurocognitive networks compared to what is found in healthy individuals, and that interaction between the SN and the striatum is even more profoundly disrupted in those with greater disease severity.

Research in animals and humans has demonstrated that the hippocampus is critical for retrieving distinct representations of overlapping sequences of information. There is recent evidence that the caudate nucleus and orbitofrontal cortex are also involved in disambiguation of overlapping spatial representations. The hippocampus and caudate are functionally distinct regions, but both have anatomical links with the orbitofrontal cortex. The present study used an fMRI-based functional connectivity analysis in humans to examine the functional relationship between the hippocampus, caudate, and orbitofrontal cortex when participants use contextual information to navigate well-learned spatial routes which share common elements. Participants were trained outside the scanner to navigate virtual mazes from a first-person perspective. Overlapping condition mazes began and ended at distinct locations, but converged in the middle to share some hallways with another maze. Non-overlapping condition mazes did not share any hallways with any other maze. Successful navigation through the overlapping hallways required contextual information identifying the current navigational route to guide the appropriate response for a given trial. Results revealed greater functional connectivity between the hippocampus, caudate, and orbitofrontal cortex for overlapping mazes compared to non-overlapping mazes. The current findings suggest that the hippocampus and caudate interact with prefrontal structures cooperatively for successful contextually-dependent navigation.

Computational models suggest the hippocampus plays an important role in the retrieval of sequences. However, empirical evidence supporting hippocampal involvement during sequence retrieval is lacking. The current study used functional magnetic resonance imaging (fMRI) to examine the role of the human hippocampus during the learning and retrieval of sequences. Participants were asked to learn four sequences comprised of six faces each. An overlapping condition, where sequences shared common elements, was comprised of two sequences in which two identical faces were shown as the middle images of both sequences. A non-overlapping condition contained two sequences that did not share any faces between them. A third random condition contained two sets of six faces that were always presented in a random order. The fMRI data were split into a learning phase and an experienced phase based upon each individuals behavioral performance. Patterns of hippocampal activity during presentation, delay, and choice periods were assessed both during learning (learning phase), and after subjects learned the sequences to criteria (experienced phase). The results revealed hippocampal activation during sequence learning, consistent with previous findings in rats and humans. Critically, the current results revealed hippocampal activation during the retrieval of learned sequences. No difference in hippocampal activation was seen between the overlapping and non-overlapping sequences during either sequence learning or the retrieval of sequences. The results extend our current knowledge by providing evidence that the hippocampus is active during the retrieval of learned sequences, consistent with current computational models of sequence learning and retrieval.