Western diet and the weakening of the interoceptive stimulus control of appetitive behavior.

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0ug but not 2.0 or 4.0ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus.

A study of hippocampal structure-function relations along the septo-temporal axis.

This study examined structural-functional differences along the septo-temporal axis of hippocampus using radial-maze tasks that involved two different memory processes [reference memory (RM) and working memory (WM)], and the use of two kinds of information (spatial vs. nonspatial cue learning). In addition, retention of the nonspatial cue task was tested nine weeks following completion of acquisition, and the rats then underwent discrimination reversal training. Ibotenic acid lesions limited to either the dorsal pole, intermediate area, or ventral pole had minimal effects on acquisition of the complex place and cue discrimination tasks. The one exception was that rats with lesions confined to the dorsal third of hippocampus made more WM errors on the spatial task (but not the cue task) early in training. Selective lesions of the three hippocampal regions had no effects on either long-term retention or reversal of the nonspatial cue discrimination task. In contrast, rats that had all of the hippocampus removed were severely impaired in learning the spatial task, making many RM and WM errors, whereas on the nonspatial cue task, the impairment was limited to WM errors. Further analysis of the WM errors made in acquisition showed that rats with complete lesions were significantly more likely on both the spatial and nonspatial cue tasks to reenter arms that had been baited and visited on that trial compared to arms that had not been baited. A similar pattern of errors emerged for complete hippocampal lesioned rats during reversal discrimination. This pattern of errors suggests that in addition to an impairment in handling spatial information, complete removal of hippocampus also interferes with the ability to inhibit responding to cues that signal reward under some conditions but not under others. The finding that selective lesions limited to the intermediate zone of the hippocampus produce no impairment in either WM ("rapid place learning") or RM in our radial maze tasks serve to limit the generality of the conclusion of Bast et al. (Bast et al. (2009) PLos Biol 7:730-746) that the intermediate area is needed for behavioral performance based on rapid learning about spatial cues.

Hippocampal lesions impair retention of discriminative responding based on energy state cues.

The present research investigated the hypothesis that the hippocampus is involved with the control of appetitive behavior by interoceptive "hunger" and "satiety" signals. Rats were trained to solve a food deprivation intensity discrimination problem in which stimuli produced by 0-hr and 24-hr food deprivation served as discriminative cues for the delivery of sucrose pellets. For Group 0+, sucrose pellets were delivered at the conclusion of each 4-min session that took place under 0-hr food deprivation, whereas no pellets were delivered during sessions that took place when the rats had been food deprived for 24 hr. Group 24+ received the reverse discriminative contingency (i.e., they received sucrose pellets under 24-hr but not under 0-hr food deprivation). When asymptotic discrimination performance was achieved (indexed by greater incidence of food magazine approach behavior on reinforced compared with nonreinforced sessions), half of the rats in each group received hippocampal lesions, and the remaining rats in each group were designated as sham- or nonlesioned controls. Following recovery from surgery, food deprivation discrimination performance was compared for lesioned and control rats in both Groups 0+ and 24+. Discriminative responding was impaired for rats with hippocampal lesions relative to their controls. This impairment was based largely on elevated responding to nonreinforced food deprivation cues. In addition, hippocampal damage was associated with increased body weight under conditions of ad libitum feeding. The results suggest that the inhibition of appetitive behavior by energy state signals may depend, in part, on the hippocampus.

Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation.

The effects of selective ibotenate lesions of the complete hippocampus (CHip), the hippocampal ventral pole (VP), or the medial prefrontal cortex (mPFC) in male rats were assessed on several measures related to energy regulation (i.e., body weight gain, food intake, body adiposity, metabolic activity, general behavioral activity, conditioned appetitive responding). The testing conditions were designed to minimize the nonspecific debilitating effects of these surgeries on intake and body weight. Rats with CHip and VP lesions exhibited significantly greater weight gain and food intake compared with controls. Furthermore, CHip-lesioned rats, but not rats with VP lesions, showed elevated metabolic activity, general activity in the dark phase of the light-dark cycle, and greater conditioned appetitive behavior, compared with control rats without these brain lesions. In contrast, rats with mPFC lesions were not different from controls on any of these measures. These results indicate that hippocampal damage interferes with energy and body weight regulation, perhaps by disrupting higher-order learning and memory processes that contribute to the control of appetitive and consummatory behavior.

Memory inhibition and energy regulation.

At a simple behavioral level, food intake and body weight regulation depend on one's ability to balance the tendency to seek out and consume food with the ability to suppress or inhibit those responses. Accordingly, any factor that augments the tendency to engage in food seeking and eating or that interferes with the suppression of these behaviors could produce (a) caloric intake in excess of caloric need; (b) increases in body weight leading to obesity. This paper starts with the idea that excess body weight and obesity stem from a failure or degradation of mechanisms that normally function to inhibit eating behavior. Unlike previous approaches, we focus not on failures of traditional physiological (e.g., neural, hormonal) regulatory control mechanisms, but on disruptions of inhibitory learning and memory processes that may help to regulate energy intake. This view of energy dysregulation as a type of "learning disorder" leads us to the hippocampus, a brain structure that has long been regarded as an important substrate for learning and memory and which we think may be critically involved with a specific type of memory inhibition function that could contribute to the suppression of food intake. With this focus, the search for environmental origins of the current obesity epidemic in Western populations is directed toward factors that alter hippocampal functioning. We conclude by offering a preliminary account of how consumption of foods high in saturated fats might lead to impaired hippocampal function, reduced ability to inhibit caloric intake and, ultimately, to increased body weight.

The hippocampus and inhibitory learning: a 'Gray' area?

Gray's approach to understanding hippocampal functioning [The Neuropsychology of Anxiety: An Enquiry into the Function of the Septo-hippocampal System, 1982; The Neuropsychology of Anxiety, 2000] departs from the prevailing view of that structure as a substrate for memory. Instead, Gray and McNaughton have proposed that hippocampus is involved with a function that is more fundamental than memory, namely the resolution of conflict between competing approach and avoidance tendencies. The present paper attempts to advance this perspective by describing how the effects of selective lesions of the hippocampus on performance in both relatively simple Pavlovian conditioning tasks and in more complex radial maze problems could be a consequence of an impairment in a simple form of inhibitory learning. Specifically, we consider the idea that the hippocampus is needed to form simple inhibitory associations between events that are concurrently embedded in simple excitatory associations [Behav Brain Res 119 (2001) 111]. This idea is compared with the conflict resolution hypothesis offered by Gray and McNaughton and avenues of integration are noted. In addition, the potential role for inhibitory learning in hippocampal-dependent spatial and contextual information processing is also discussed.

Functional differentiation within the medial temporal lobe in the rat.

The structures that comprise the medial temporal lobe (MTL) have been implicated in learning and memory. The question of primary concern in the present research was whether the group of anatomically related structures (hippocampus, subiculum, presubiculum/parasubiculum, entorhinal cortex, perirhinal/postrhinal cortex) are involved in mediating a similar memory process or whether the individual structures are differentially involved in memory processes and/or in handling various types of information. A series of five experiments were carried out that involved selectively lesioning the main MTL structures and testing each animal on radial-maze tasks and procedures that provided measures of two different memory processes (reference memory, working memory) and the utilization of two kinds of information (spatial, nonspatial). The structures were found to differ functionally, with the hippocampus and the presubiculum/parasubiculum being especially involved in processing spatial information, and the perirhinal/postrhinal cortex having a specific role in remembering information over a brief time period (working memory). Lesions of the entorhinal cortex failed to affect consistently either memory process or type of information handled, but they did result in impairments in learning the complex spatial discrimination requiring reference memory and in working memory involving nonspatial information. The pattern of behavioral impairments resulting from damage to these discrete MTL structures suggests that several of the structures make unique contributions to learning and memory.

Perirhinal cortex supports delay fear conditioning to rat ultrasonic social signals.

Auditory information can reach the lateral nucleus of the amygdala (LA) through a monosynaptic thalamic projection or a polysynaptic cortical route. The polymodal input from the perirhinal cortex (PR) is a major informational gateway to the LA and nearby structures. Pretraining PR lesions impair fear conditioning to a context, but there have been no reports that they cause deficits in delay conditioning to an auditory cue. The direct subcortical projection to the LA seems sufficient to support delay conditioning to a tone conditional stimulus (CS). We examined the effect of PR lesions on delay conditioning to two different tone conditional stimuli (4 and 22 kHz tones; both 10 sec duration) and two different rat ultrasonic vocalization (USV) conditional stimuli (10 sec of "22 kHz USVs"). The two USV conditional stimuli were multi-call segments that were recorded (digitized at 100 kHz) from two different rats. One USV CS was a continuous sequence of eight calls, and the other was a portion of a continuous sequence of six calls. PR lesions significantly impaired conditioning to both USV conditional stimuli and to the training context but had no significant effect on conditioning to either tone CS. The role of PR in fear conditioning appears not to be determined by whether the conditional stimuli serve as contexts or cues, but instead by the nature or complexity of the stimuli or stimulus configurations. These cue-specific effects of PR lesions are suggested to reflect differences in the stimulus features that are encoded in the two CS pathways to the LA.

Excitotoxic lesions of the pre- and parasubiculum disrupt the place fields of hippocampal pyramidal cells.

To determine what influence the pre- and parasubiculum regions of the hippocampal formation have on neural representations within the dorsal hippocampus, single-unit recordings were made as rats with bilateral ibotenic acid lesions centered on the former regions (n = 4) or control surgeries (n = 3) foraged freely. Spatial firing specificity was measured using an information content procedure. Cells from lesioned animals (n = 57) provided significantly less spatial information than cells from control animals (n = 44). Whereas some degree of location-related activity (place fields) was observed in 98% of neurons recorded from control animals, it was observed in only 65% of the neurons from lesioned animals. The spatial resolution of the intact place fields appeared to be compromised in lesioned animals as a result of their having a higher firing rate outside the place field. These findings indicate that the pre- and parasubiculum regions have a major role in maintaining the specificity of the place field firing of hippocampal pyramidal cells. Since previous data indicate that these lesioned animals displayed delay-dependent deficits in spatial tasks, these findings also suggest that a disruption in place field activity may be a causal factor in this spatial memory deficit.

Use of excitotoxins to lesion the hippocampus: update.

Although many of the problems associated with the use of conventional lesion techniques (aspiration, electrolytic, radiofrequency) can be avoided by employing focal injections of excitotoxins, experience gained over the past 12 years has shown that considerable care must be exercised with this newer method, to limit the cell loss to the intended area or structure. Of the toxins that have been used most often to selectively destroy the cells that comprise the hippocampus, ibotenic acid (IBO) and N-methyl-D-aspartate (NMDA) have proved to be nonspecific in their effects on different cell types and these toxins do not cause seizures. In contrast, focal injections of kainate (KA) and quisqualate result in damage that centers primarily in the CA3 pyramidal cell field and hilar cells in the dentate gyrus. In addition, there are obvious seizures and secondary distant damage involving a number of structures and areas associated with mediating seizure activity. Intrahippocampal injections of the toxin colchicine result in a preferential destruction of dentate granule cells but usually also lead to additional cell loss in adjacent areas. Attempts to limit cell loss to specific hippocampal subfields, using different toxins, have met with mixed success. Both the dosage of the agent and the volume injected are important in determining the extent of cell loss, but the volume of the toxin injected has been shown to be especially important in limiting the damage to the intended area. With the development of newer procedures (e.g., immunotoxins, gene knockouts, antisense) that permit more selective cell loss, it should be possible in the future to achieve a level of lesion control that has been lacking in the past. As with the use of excitotoxins, these newer approaches will require special care to limit the damage to the intended area and interpret the results obtained properly.