What happens if the lateral hypothalamus is destroyed

The SFO and OVLT are sensory circumventricular organs, or brain areas that lack a true blood-brain barrier Johnson and Gross, which allows them to monitor substances in the blood that act as indicators of body fluid status Johnson and Thunhorst, , It is also worth noting here that there is currently debate as to whether the ARH lacks a blood-brain barrier and is a true circumventricular organ Mimee et al.

As such, it has been proposed that the LT may also function to detect signals related to energy balance Mimee et al. It is important to realize that the ingestion of food, water, and sodium require coordinated activity between neural circuits that sense energy and fluid status and the neural circuitry involved in mobilizing motivated behaviors Garcia et al.

Therefore, the brain areas that monitor fluid and energy status must be able to project onto the areas that regulate motivation and reward. One final common pathway that is implicated in the generation of all appetitive motivated behaviors investigated thus far is the dopaminergic projection from the ventral tegmental area VTA to the nucleus accumbens AKA the mesolimbic dopamine system and the A10 dopaminergic cell group; Mogenson et al.

For example, retrograde tracing studies have shown that a large region of the hypothalamus contains neurons that project to the VTA Geisler and Zahm, This region extends from the dorsomedial hypothalamus DMH to the dorsal region of the lateral hypothalamus LHAd and appears to be present across the entire anterior-posterior extent of the hypothalamus.

In a classic paper, Stellar proposed a hypothalamus-centered theory of motivation. For example, he posited that the hypothalamus contained centers that specifically control sex, satiety, hunger, and sleep. Classic experiments that employed short bursts of electrical stimulation directed at the lateral hypothalamic area LHA demonstrated that the LHA is involved in motivation and reward processes.

Olds and Milner originally found that rats will perform an operant to obtain acute electrical stimulation of the LHA, an experimental paradigm sometimes referred to as self-stimulation or brain stimulation reward. They interpreted their finding to mean that electrical stimulation of the LHA was rewarding i. If this assessment is correct, it would suggest that some neurons within the LHA are functionally important for coding pleasure from the consumption of rewards.

However, others have suggested LHA stimulation may actually produce a subjective state of craving rather than pleasure per se Berridge and Valenstein, If this interpretation is true it would suggest that a subset of neurons located in the LHAd are involved in the craving that drives animals to seek rewards. It is likely that the motivational and rewarding properties of LHA stimulation are the result of the activation of neurons in the LHA that project to the mesolimbic dopamine system Phillipson, ; Geisler and Zahm, Furthermore, lesions of the LHA abolish food and water intake, copulation, and impair or abolish sodium appetite Anand and Brobeck, ; Montemurro and Stevenson, ; Teitelbaum and Epstein, ; Wolf, ; Wolf and Quartermain, ; Cagguila et al.

Disruptions in energy or fluid balance alter responding for self-stimulation Olds, ; Morris et al. Olds originally found that food-depriving rats and inducing the motivational state of hunger increased responding for self-stimulation. Furthermore, increased responding for self-stimulation during food deprivation can be prevented by administration of leptin, a hormone that promotes satiety Fulton et al.

In contrast to food deprivation, sodium depletion reduces responding for self-stimulation Morris et al. Reduced responding for self-stimulation is even observed when rats are made salt hungry through administration of an exogenous hormone that promotes salt appetite; despite the fact rats maintain sodium balance during this treatment Morris et al. It is unclear as to why the motivational states of hunger and salt appetite produce opposite effects on self-stimulation.

However, these studies demonstrate that hunger and salt appetite alter self-stimulation responding and this effect appears to be independent of actual disruptions in energy or fluid homeostasis. For example, leptin normalizes self-stimulation responding without correcting lost calories Fulton et al.

Some of the strongest evidence supporting a role for the hypothalamus in promoting motivated behavior comes from studies examining orexin AKA hypocretin. Orexin is a neuropeptide that is expressed primarily in the caudal half of the hypothalamus where it is distributed in an arc that extends from the DMH to the LHAd Figure 1. Orexin appears to be the only known centralized peptide neurotransmitter system as orexin neurons from a relatively circumscribed area send distal projections to diverse brain areas Peyron et al.

Functionally, orexin neurons have been heavily implicated in a variety of motivated behaviors Harris et al. Orexin has received significant attention for its capacity to elicit robust food intake hence the name orexin; Sakurai et al. Each orexin cell-cluster contains a subset of orexin neurons that project to the VTA Figure 1 ; Fadel and Deutch, , and orexin is capable of depolarizing neurons in the VTA Korotkova et al.

Therefore, orexin neurons provide a mechanism for areas within the LHA to tap into systems traditionally conceived of as being involved in motivation and reward.

Evidence also indicates that orexin neurons have direct projections to the nucleus accumbens shell Peyron et al. Figure 1. Unpublished data from authors.

Co-labeling between orexin and VTA projection neurons in the hypothalamus. Images A—I were taken at 10x magnification and images J—L were taken at 40x. Double-labeled neurons are indicated by white arrows. Other major functions of orexin include promoting arousal Hagan et al.

It is likely that orexin neurons are activated while an animal is experiencing caloric, hydrational, or sodium deficiency or is in a state of sexual arousal. The subsequent release of orexin throughout the neuraxis encourages the performance of goal-directed behavior by activating brain systems involved in promoting arousal, attention, sympathetic activity, and motivated behavior. Sympathetic activation supports energy mobilization e. Together these central and peripheral responses serve to increase the likelihood that an animal will successfully seek out and consume environmental reinforcers that restore energy and hydrational homeostasis.

Anatomical and immunohistochemical studies support the idea that the LHA aids in integrating signaling from orexigenic peptides with neurocircuitry involved in motivation and reward. Treatments that induce hunger such as hypoglycemia or administration of orexigenic peptides including ghrelin and NPY induce c- fos expression in orexin-containing neurons Moriguchi et al.

Additionally, compromising orexin neurotransmission attenuates feeding induced by administration of either NPY or ghrelin. Figure 2. Images were taken at different magnifications to compensate for the size of the brain area. In contrast to studies on food intake, relatively little work has been done delineating how the LT may influence motivation and reward neural circuitry.

Furthermore, recent experiments in our laboratory have shown that iontophoretic application of the retrograde tracer Fluoro-Gold into the posterior portion of the DMH, PeF, and LHAd reveals retrograde labeling across the entirety of the LT an example of retrograde labeling from an injection that spread from the PeF to the LH is presented in Figure 2.

Additionally, we have recently found that orexin neurons are activated when rats depleted of water and sodium are allowed to ingest water and hypertonic saline and that microinjection of an orexin receptor antagonist into the VTA attenuated combined water and sodium intake in depleted rats Hurley et al.

Orexin release in the VTA promotes the ingestion of water and sodium. These experiments provide both anatomical and functional support to the hypothesis that the LHA integrates information about homeostatic state with motivation and reward systems.

Experiments that examined the effect of sustained LHA stimulation on motivated behaviors provided some of the earliest evidence that the LHA may be involved in reward-related learning. When individual rats receive LHA stimulation they initially exhibit one specific motivated behavior Valenstein et al.

Some rats will eat, while others will drink or engage in copulatory behaviors. The motivated behavior each rat engages in is referred to as the prepotent behavior.

Importantly, the prepotent behavior performed during LHA stimulation can be modified by experience Valenstein et al. If the preferred goal object is removed during LHA stimulation, rats will direct their motivated behavior towards another goal object that is present in the environment.

For example, if a rat eats during LHA stimulation, food can be removed while a drinking spout remains. In this situation the stimulated rat will now drink from the spout. Importantly, when the LHA is stimulated in future trials when both food and water are present, the rat will essentially split its time between eating and drinking. Therefore, pairing LHA stimulation with the presence of an initially non-preferred goal object causes a rat to direct some of its behavior toward the previously ignored goal object.

It appears that LHA stimulation and the subsequent consumption of a goal object results in a form of associative learning that is expressed through changes in prepotent behaviors. Orexin neuron activation can also become conditioned to stimuli in the environment. In conditioned place preference paradigms a novel environmental context is associated with a reward. After repeated pairings of an environmental context with a reward, rats will exhibit a preference for the context that was paired with reward.

The preference that develops in conditioned place preference paradigms appears to be associated with orexin neuron activation. Orexin neurons express c- fos in response to environmental contexts that have become associated with drugs of abuse and sex Harris et al.

Furthermore, lesioning orexin neurons with an orexin conjugated-saporin prevents male rats from exhibiting a conditioned place preference for an environmental context associated with copulation Di Sebastiano et al. Further evidence supporting LHA involvement in associative forms of reward learning comes from the phenomenon of cue-induced feeding.

In the cue-induced feeding paradigm, food-deprived rats are allowed to eat in the presence of an environmental cue. The LHA is one area that is critical for the performance of cue-induced feeding Petrovich and Gallagher, ; Petrovich et al. The LHA receives inputs from areas involved in associative forms of reward-learning including the amygdala Krettek and Price, ; Everitt et al.

In addition, contralateral asymmetrical lesions of the basolateral amygdala and LHA prevent cue-induced feeding Petrovich et al.

Finally, the LHA has been implicated in non-associative forms of reward-related learning. When rats are repeatedly depleted of sodium they exhibit an increase in sodium intake Falk, ; Sakai et al. Sensitization of sodium appetite is likely to be a form of non-associative learning Falk, ; Frankmann et al.

Evidence suggests that sodium appetite sensitization involves neural plasticity in two neural circuits: one circuit governing body fluid homeostasis and another circuit mediating motivation and reward Roitman et al. Furthermore, rats with a history of sodium depletions exhibit enhanced dendritic arborization and length in the nucleus accumbens Roitman et al.

Many of the areas that appear to undergo sensitization during sodium depletion also send projections to the LHA, including the SFO, prefrontal cortex, and basolateral amygdala. The LHA sends projections to the VTA, which in turn is capable of inducing neural plasticity in nucleus accumbens neurons Mameli et al. Finally, additional evidence supports the possibility that orexin neurons undergo neural plasticity from sodium depletion Liedtke et al.

Activity-regulated cytoskeleton-associated protein, which plays a critical role in neural plasticity Tzingounis and Nicoll, ; Shepherd and Bear, , is upregulated in PeF orexin neurons during sodium depletion Liedtke et al.

The reviewed experiments support the hypothesis that the LHA contributes to the integration of information related to homeostatic state and past experience with motivation and reward systems. A summary of the anatomical and functional data is presented in Figure 3. Nuclei within the LHA, including the PeF and LHAd, receive projections from brain areas that regulate energy and body fluid homeostasis in addition to areas involved in associative learning Broberger et al.

Although Figure 3 displays a hierarchical model of LHA functioning dominated by efferent connections to downstream brain areas, it may be the case that this circuitry is actually a neural network which consists of bidirectional inputs between areas involved in learning, homeostasis, and motivation and reward.

In this respect, the use of anterograde and retrograde tracer co-injections would provide utility in identifying whether these areas form a neuronal network for example see Thompson and Swanson, Figure 3. A schematic summary of the reviewed experiments. Areas involved in associative learning green and maintaining homeostasis blue project to the LHA.

The LHA sends projections to motivation and reward areas red to initiate motivated behaviors. The LHA also sends projections to the nucleus accumbens that may promote motivated behaviors dashed line. As orexin is not exclusively involved in mediating just a single motivated behavior, it is likely that orexin acts to strengthen goal-directed responses associated with several motivated states Borgland et al.

Cues related to reward presentation and consumption can also induce activation of orexin neurons Harris et al. Therefore, there are at least two conditions that induce orexin neuron activity: 1 the actual seeking and consumption of rewards; and 2 learned associations with rewards. With respect to the second point it is important to point out that orexin can induce neural plasticity in the VTA itself Borgland et al. It is unlikely that orexin mediates all of the effects on motivated behaviors observed through manipulations of the LHA, as many projections from the hypothalamus to the VTA are non-orexinergic.

Future work that aims to carefully investigate the role of nuclei located within the LHA will prove fruitful. The LHA actually consists of a collection of heterogeneous brain areas that have unique neuroanatomical connections and cytoarchitecture Swanson et al.

Furthermore, it appears that separate orexin neuron clusters are activated under different experimental conditions Harris et al.

Optogenetic manipulations provide a method to test whether these orexin cell clusters have a functionally significant projection to the VTA or nucleus accumbens. Additionally, inactivation of orexin cell clusters should influence the activity of VTA and nucleus accumbens neurons. Finally, it is worth noting that many of the discussed experiments did not dissociate and define the roles of brain nuclei within the LHA and did not discuss the role of the DMH in motivated behaviors.

The DMH also receives projections from body fluid homeostasis areas Swanson and Lind, , sends projections to the VTA Geisler and Zahm, , and contains orexin neurons Fadel and Deutch, , all of which are potentially involved in homeostatic behaviors. From a behavioral perspective, some disorders can be conceived of as problems of ingestion. For example, anorexics fail to ingest sufficient amounts of food while those suffering from obesity ingest too much food.

Similarly, some individuals ingest far too much sodium; a phenomenon sometimes referred to as salt gluttony Schulkin, , while others ingest too little sodium and consequently become sodium deficient causing them to experience autonomic and cardiovascular dysfunction Bou-Holaigah et al.

Additionally, elderly individuals may exhibit diminished thirst and subsequent dehydration Rolls and Phillips, ; Warren et al. One approach to understanding these maladies that are marked by a surplus or surfeit in ingestive behavior is to conceive of them as problems of central nervous system functioning related to maintaining homeostasis and appropriately engaging in motivated behavior.

As the LHA is critically involved in both maintaining homeostasis and mediating motivated behaviors, an improved understanding of the LHA may aid in diagnosing and treating disorders of ingestion. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors thank Young In Kim for her technical assistance and Marilyn Dennis for comments on the manuscript.

The authors have no disclosures to report. Anand, B. Hypothalamic control of food intake in rats and cats. Yale J. Beauchamp, G. Experimental sodium depletion and salt taste in normal human volunteers. Berridge, K. Sodium depletion enhances salt palatability in rats. Palatability shift of a salt-associated incentive during sodium depletion. B 41, — What psychological process mediates feeding evoked by electrical stimulation of the lateral hypothalamus? Bindra, D.

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Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49, — Bou-Holaigah, I.

The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA , — Bozarth, M. Broberger, C. Brog, J. Cagguila, A. Disruption of copulation in male rats after hypothalamic lesions: a behavioral, anatomical and neurochemical analysis.

Brain Res. Choi, D. The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience , 11— Clark, J. Denton, D. Hypothalamic integration of body fluid regulation. U S A 93, — Di Sebastiano, A. Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats. Orexin mediates initiation of sexual behavior in sexually naive male rats, but is not critical for sexual performance.

Everitt, B. Associative processes in addiction and reward the role of amygdala-ventral striatal subsystems. N Y Acad. Fadel, J. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience , — Falk, J. Water intake and NaCl appetite in sodium depletion. Serial sodium depletion and NaCl solution intake. Fanselow, M. Flavor-flavor associations induce hedonic shifts in taste preference.

Ferguson, A. Frankmann, S. Epstein and M. Fulton, S. Modulation of brain reward circuitry by leptin. Science , — Gallagher, M. Orbitofrontal cortex and representation of incentive value in associative learning. Garcia, J. Behavioral regulation of the milieu interne in man and rat. If you have a lot of body fat, especially in the belly area, then you are almost certainly leptin resistant. Leptin, a related fat hormone, has been widely studied in recent years and has been shown in to produce weight loss in animals by decreasing appetite and increasing metabolism.

Researchers say both fat hormones work through the same pathway in the brain to control body weight and blood sugar glucose. Begin typing your search term above and press enter to search. Press ESC to cancel. Skip to content Home Physics When the lateral hypothalamus is destroyed rats will group of answer choices?

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