The human orbitofrontal cortex (OFC) is known to play a critical role in goal-directed behavior. However, it is still unknown whether the OFC contribution to guiding behavior is through top-down control of inappropriate responses or through providing a motivational context by representing potential outcomes. This dilemma stems from the fact that research to date has not been able to clearly distinguish the effects of changes in motivational states from associated adjustments in cognitive control. In order to answer this question, two functional magnetic resonance imaging (fMRI) studies, simultaneously and independently manipulated demands for inhibitory control and monetary incentives for correct performance. Across experiments, demands for control only engaged the OFC when they also increased the likelihood of a negative outcome, in the form of increased error rates. In contrast to these effects of control, expected outcomes modulated the OFC activity irrespective of whether the demands for control were high or low. Moreover, the lateral areas of the OFC were maximally engaged during expectation of negative outcomes. Thus, we provided convergent evidence that the OFC is specifically involved in establishing the motivational context of behavior through representation of possible outcomes. Furthermore, the nature of outcome representations in these two experiments have potential implications for existing theories of decision making, by providing evidence that the OFC iii representations of potential outcomes are influenced the whole range of possible alternative outcomes. In a third fMRI experiment, the framework laid out by the first two studies was applied in the analysis of data investigating the neural substrates of obsessive-compulsive disorder (OCD). Compared to control subjects, the OFC of patients showed increased activity in response to stimuli associated with relatively increased potential for negative outcomes, despite the fact that those stimuli were not directly relevant to obsessive-compulsive symptomatology. These findings suggest that the OFC hyperactivity in OCD may reflect an underlying neural dysfunction, and are consistent with the phenomenology of this disease, in which excessive concerns for potential negative outcomes of actions are a prominent feature of symptomatology.

The mediodorsal nucleus of the thalamus (MD) represents the main subcortical structure that projects to the prefrontal cortex (PFC) and regulates key aspects of the cognitive functions of this region. Within the PFC, GABA local circuit neurons shape the activity patterns and hence the memory fields of pyramidal cells. Although the connections between the MD and PFC are well established, little attention has been given to the functional connections between projecting fibers from the MD and different subclasses of GABA cells in the PFC. In order to address this issue in the rat, we examined MD axons labeled by tract-tracing in combination with immunogold-silver to identify different calcium binding proteins localized within separate populations of interneurons. Electron micrographic examination of PFC sections from these animals revealed that MD terminals made primarily asymmetric synapses onto dendritic spines and less commonly onto dendritic shafts. Most of the dendrites receiving MD synaptic input were immunoreactive for parvalbumin (ParV), whereas dendrites labeled for calretinin or calbindin received synapses from MD fibers less frequently. We also observed that some MD terminals were themselves immunoreactive for calcium binding proteins, again more commonly for ParV. These results suggest that the MD exerts a dual influence on PFC pyramidal cells: direct inputs onto spines and an indirect influence mediated via synapses onto each subclass of interneurons. The preferential input to ParV cells endows MD afferents with a strong indirect influence on pyramidal cell activity by virtue of ParV cell synapses onto soma, proximal dendrites and axon initial segments.

Changes in posture are detected by the central nervous system through a number of sensory afferents. The vestibular labyrinths are one such sensor that discern rotational and accelerative movements of the head. The vestibular nuclei, the primary processor of labyrinthine input, coordinates several system outputs to maintain stable balance, visual gaze, and autonomic control in response to changes in posture. Following destruction of bilateral labyrinths, organisms are unable to effectively interact with their environment. Over time, these animals adapt due to some currently undefined process. It is our hypothesis that the observed behavioral recovery is due to a process that occurs within the vestibular nuclei. The nuclei regain their functional ability to sense changes in posture through substitution of sensory inputs from remaining non-labyrinthine afferents. Ascending spinovestibular afferents are ideal sources of plasticity, as they are ideally situated to convey this postural information. Recordings were made from the vestibular nuclei of decerebrate cats that had undergone a combined bilateral labyrinthectomy and vestibular neurectomy 49103 days previously and allowed to recover. Responses of neurons were recorded to tilts in multiple vertical planes at frequencies ranging from 0.05 to 1 Hz and amplitudes up to 15°. The firing of 27% of the neurons was modulated by tilt. These findings show that activation of vestibular nucleus neurons during vertical rotations is not exclusively the result of labyrinthine inputs, and suggest that limb and trunk inputs may play an important role in graviception and modulating vestibular-elicited reflexes. In the second portion of this work, we examined the spinal contributions to the vestibular nuclei in both labyrinthectomized and normal animals. The large majority (72%) of vestibular nucleus neurons in labyrinth-intact animals whose firing was modulated by vertical rotations responded to electrical stimulation of limb and/or visceral nerves; the activity of even more vestibular nucleus neurons (93%) was affected by limb or visceral nerve stimulation in chronically labyrinthectomized preparations. These data suggest that nonlabyrinthine inputs elicited during movement will modulate the gain of responses elicited by the central vestibular system, and may provide for the recovery of spontaneous activity of vestibular nucleus neurons following peripheral vestibular lesions.

Recent experiments in neurophysiology have begun to examine the active nature of our perceptual experience. One area of research focuses on the impact of eye movements on visual perception. With each eye movement, a new image is presented to the brain, yet our perception is that the world remains stable. This phenomenon, termed spatial constancy, depends on a convergence of information about our eye movements with sensory information from the visual system. Neurons in the lateral intraparietal cortex (LIP) contribute to the construction of an internal representation of space that is updated or remapped with each eye movement. Although the basic phenomenon of remapping has been described, many questions remain unanswered. Here we describe two experiments designed to gain a greater understanding of spatial updating in the primate brain. First, we hypothesized that spatial updating would be equally robust throughout the visual field. We tested this by monitoring the activity of neurons in LIP while varying the direction over which a stimulus trace must be updated. We found that individual neurons remap stimulus traces in multiple directions, though the strength of the remapped response is variable. Across the population of LIP neurons, remapping is effectively independent of saccade direction. These findings indicate that the activity of LIP neurons can contribute to the maintenance of spatial constancy throughout the visual field. Second, to begin to understand the circuitry underlying remapping, we studied a special case: when a stimulus must be updated from one visual hemifield to the other. We hypothesized that the forebrain commissures provide the primary route for this across-hemifield remapping. We tested this by comparing the signal related to within- and across-hemifield remapping. We predicted that in split-brain monkeys, across-hemifield remapping would be abolished while within-hemifield remapping would remain robust. Surprisingly, we found that in split-brain monkeys, LIP neurons can remap stimulus traces across hemifields, though this signal is weaker than that associated with within-hemifield remapping. This finding implies that while the forebrain commissures are likely to be the primary route for the interhemispheric transfer of visual information, they are not the only route available. This indicates that a distributed network of brain regions supports spatial updating.

The frontal eye field (FEF) has been implicated as a possible participant in attentional allocation. Recent studies have found that low-current stimulation of FEF results in enhanced attention and increased visual responses in extrastriate visual area V4. We investigated the necessity of FEF function for allocating attention by unilaterally inactivating FEF in two monkeys and testing the monkeys ability on a two-alternative forced-choice saccade task. This task was designed to spatially dissociate two processes which we assessed separately: discrimination of a visual cue and generation of a saccade. Following inactivation, we determined the extent of contralesional saccadic deficits, compared to contralesional discrimination deficits, using a choice-based analysis and a reaction time (RT)-based analysis. Overall, we found that unilateral inactivation had an impact on contralesional saccadic performance corresponding to a 61.7-ms overall change in RT and a 34% change in choice probability. On the other hand, we discovered only a 7.0-ms overall change in RT and a 0% change in choice probability with respect to contralesional visual discrimination ability. We conclude that FEF function is much more important for saccadic generation than attentional allocation.

Single neurons in several cortical areas in monkeys update visual information in conjunction with eye movements. This remapping of stimulus representations is thought to contribute to spatial constancy. The central hypothesis here is that spatial updating also occurs in humans and that it can be visualized with functional MRI. In Chapter 2, we describe experiments in which we tested the role of human parietal cortex in spatial updating. We scanned subjects during a task that involved remapping of visual signals across hemifields. This task is directly analogous to the single-step saccade task used to test spatial updating in monkeys. We observed an initial response in the hemisphere contralateral to the visual stimulus, followed by a remapped response in the hemisphere ipsilateral to the stimulus. Our results demonstrate that updating of visual information occurs in human parietal cortex and can be visualized with fMRI. The experiments in Chapter 2 show that updated visual responses have a characteristic latency and response shape. Chapter 3 describes a statistical model for estimating these parameters. The method is based on a nonlinear, fully Bayesian, hierarchical model that decomposes the fMRI time series data into baseline, smooth drift, activation signal, and noise. This chapter shows that this model performs well relative to commonly-used general linear models. In Chapter 4, we use the statistical method described in Chapter 3 to test for the presence of spatial updating activity in human extrastriate visual cortex. We identified the borders of several retinotopically defined visual areas in the occipital lobe. We then tested for spatial updating using the single step saccade task. We found a roughly monotonic relationship between the strength of updating activity and position in the visual area hierarchy. We observed the strongest responses in area V4, and the weakest response in V1. We conclude that updating is not restricted to brain regions involved primarily in attention and the generation of eye movements, but rather, is present in occipital lobe visual areas as well.

The present experiments sought to identify the physiological signals that inhibit thirst when dehydrated rats drink water or NaCl solution. Rats were deprived of drinking fluid but not food overnight. When allowed to drink again, the dehydrated animals consumed water or saline (0.05 M, 0.10 M, 0.15 M, or 0.20 M NaCl solution) almost continuously for 5-8 min before stopping. The volumes consumed were similar regardless of which fluid they ingested, but blood analyses indicated that increased plasma osmolality and decreased plasma volume, or both, still remained when drinking terminated. These results suggest that the composition of the ingested fluid is less significant than its volume in providing an early signal that inhibits thirst and fluid consumption by dehydrated rats. Analyses of the gastrointestinal tracts revealed that the cumulative volume in the stomach and small intestine correlated highly with the amount consumed regardless of which fluid was ingested. These and other results suggest that the volume of fluid ingested by dehydrated rats is sensed by stretch receptors detecting distension of the stomach and small intestine, which provide an early inhibitory stimulus of thirst.

NA inputs to the BNST are implicated in stress and anxiety. The alpha-2 adrenoceptor antagonist YO increases transmitter release from NA terminals, activates the HPA axis, and is anxiogenic. We have shown that YO dose-dependently activates Fos in the BNST and PVN. We also have shown that YO inhibits food intake and supports conditioned flavor avoidance. Recruitment of NA inputs to the BNST may underlie these neural and behavioral effects of YO. In the present study, NA inputs to the ventrolateral BNST were lesioned bilaterally by microinjecting saporin toxin conjugated to DBH antibody (DSAP). Ten to 14 days after surgery, DSAP (n=9) and sham rats (n=7) were food-deprived for 24 hrs. Half of the rats in each group were injected i.p. with saline vehicle, and half were injected with YO (5.0 mg/kg). Food was returned 30 min later, and cumulative intake was recorded. The experiment was later repeated in a counterbalanced design. YO significantly inhibited food intake to a similar extent in sham and DSAP rats. The second experiment examined the ability of YO to support conditioned flavor avoidance. In a two-bottle choice test, water-deprived rats significantly avoided drinking water containing flavors previously paired with YO treatment. The magnitude of conditioned aversion was similar in DSAP and sham rats. The third experiment examined YO-induced anxiety-like behaviors on the elevated plus maze. DSAP and sham rats were acclimated to handling, transport and timecourse of the experiment for 3 days prior to the first test day. Rats were left undisturbed in a room adjacent to the testing room for 30 minutes. Then, each rat was injected i.p. with either YO or saline. Thirty minutes after injection rats were placed on the elevated plus maze for 5 minutes while being recorded. YO-induced increases in anxiety-like behavior were attenuated in DSAP rats. Finally, DSAP and sham rats were injected with YO or vehicle and perfused with fixative 90120 minutes later. Brain sections were processed to reveal lesion extent and Fos activation patterns. YO activated significantly fewer BNST neurons and CRH-positive PVN neurons in DSAP rats compared to sham controls. DBH immunolabeling in the BNST and medial parvocellular PVN was depleted in DSAP rats, whereas the lateral magnocellular PVN was unaffected. The NST and VLM contained significantly fewer NA neurons in DSAP rats compared to sham controls; however, YO activated similar proportions of the NA neurons that remained. We conclude that NA neurons innervating the BNST collateralize to innervate the medial parvocellular PVN, and that these NA inputs are necessary for YO to activate Fos within the BNST and PVN. Additionally, these inputs contribute to the YO-induced anxiety-like behaviors on the elevated plus maze. However, the NA inputs to the BNST are unnecessary for YO to inhibit food intake or support conditioned flavor avoidance, suggesting that other neural pathways are sufficient for these responses.

The inferotemporal cortex of the macaque monkey mediates the recognition of objects in the visual world. The purpose of the research presented in this dissertation was to investigate the neural mechanisms underlying two poorly understood aspects of object recognition. The first experiment addressed the question of how visual features are integrated in IT. In this study, we sought to determine whether feature selectivity for shape and color is integrated by IT neurons via a conjunction-coding mechanism, or via linear summation. We demonstrate that visual responses of most IT neurons encode shape and color information in a linear manner. Our results shed light on the computational strategy that the brain employs to construct a versatile representation of the visual world. The purpose of the second experiment was to investigate the neural mechanisms underlying repetition priming. Repetition priming is a form of rapid visual learning, whereby previous experience with an object allows for faster, more efficient perceptual processing of that object upon subsequent encounters. This behavioral process is believed to be dependent on activity reductions in single IT neurons, but this hypothesis has never been tested. Indeed, repetition priming has never been demonstrated before in monkeys. To address this issue, we adapted the experimental paradigm of repetition priming for use in primate physiology. We demonstrate that repetition priming at the level of behavior is accompanied by repetition suppression at the level of single neurons in IT. We further demonstrate that repetition suppression in IT results in a proportional scaling reduction of visual responses, and not in a sharpening of the stimulus selectivity. These findings constrain the possible mechanisms whereby visual response plasticity in IT could contribute to behavioral priming.

Recent studies have shown that when dehydrated rats are given access to water or various concentrations of saline solution, they consume the same volume of fluid in an initial drinking bout (Hoffmann et al., 2006). Furthermore, there was a close relation between fluid intake and distension of the stomach and small intestine when dehydrated rats drank water or saline (Hoffmann et al., 2006). These results are consistent with the hypothesis that fluid ingestion is constrained by a rapid inhibitory signal associated with GI fill. This volume-dependent early inhibition of thirst is reminiscent of the volume-dependent oropharyngeal reflex that Ramsay and colleagues described in dogs (Thrasher et al., 1981). Other studies (Huang et al., 2000) have shown that rats infused iv with hypertonic saline develop a strong motivation to consume water and show a marked increase in pVP. After water ingestion, pVP decreased rapidly before there was a change in systemic pOsm. Plasma VP remained elevated in rats that were given isotonic saline to drink. These results are consistent with the hypothesis that VP secretion is rapidly inhibited when dilute fluid enters the GI tract. The present studies sought to determine whether an early inhibition of fluid consumption by hypovolemic rats also was associated with GI fill. We imposed a 16-hr delay between the time that PEG solution was injected and the start of the drinking test. These animals have a substantial volume deficit (30-40%) as well as increased circulating levels of VP, OT, AngII, and aldosterone. Therefore, they have a pronounced thirst and salt appetite and will be eager to consume large volumes of fluid rapidly, thus allowing us to determine whether 1) distension of the stomach and small intestine provide a rapid inhibitory feedback signal for thirst and salt appetite, 2) gastric emptying of water or 0.30 M NaCl solution provide a presystemic signal that influences VP secretion, 3) changes in systemic pOsm influence ingestive behavior or VP secretion in rats with prolonged hypovolemia, and 4) GI fill continues to act as an inhibitory signal for fluid consumption after the first drinking bout.