Dopamine and ACH involvement in plastic learning by hypothalamic neurons in rats

Unit activity in the rat lateral hypothalamus (LHA) was recorded during discrimination learning of cue tone stimuli (CTS). CTS+ predicted reward (glucose or intracranial self-stimulation); CTS- predicted aversion (electric shock or tail pinch); and all behavior responses were by the same act, licking. Roles of the LHA dopaminergic and cholinergic systems in CTS learning were investigated by electrophoretic application of dopamine (DA) and acetylcholine (ACh), and their antagonists. The CTS+, the predicted reward and DA, all had similar effects (inhibition) on many LHA neurons; and these were all opposite to the effects (excitation) of CTS-, the predicted aversion, and ACh. Neural responses to CTS+ were blocked by spiperone, and responses to CTS- were blocked by atropine. Sensitivity of LHA neurons to DA was reduced by extinction of CTS+ learning for reward, and sensitivity to ACh was reduced by CTS- learning for aversion. The data suggest that afferent DA and ACh inputs to LHA neurons are essential for plastic CTS+ and CTS- learning.     

Central action of endogenous sugar acid (2-buten-4-olide): comparison with local anesthesia in hypothalamus

Rats were trained to discriminate cue tone stimuli (CTS) predicting reward (CTS+) [juice or intracranial self-stimulation (ICSS)], or aversion (CTS-) (mild electric shock or tail pinch). Unit activity in the lateal hypothalamus (LHA) and lateral preoptic-anterior hypothalamic area (lPOA-AHA) of the rat was recorded during CTS learning. The effects of local anesthesia of the amygdala (AM), ventral tegmental area (VTA) or LHA by procaine hydrochloride, and the effects of intraperitoneal or intravenous 2-buten-4-olide (2-B4O) on LHA neural activity and licking behavior were compared. LHA neurons differentiated between rewarding and aversive stimuli, and acquired corresponding discrimination of CTS+ and CTS-. In the lPOA-AHA, neurons responded similarly to CTS+, rewarding stimuli, CTS- and aversive stimuli. Procainization of the AM suppressed LHA neural responses to CTS1+ predicting juice, and stopped licking for juice. Procainization of the VTA suppressed LHA neural responses to CTS2+ predicting ICSS, and stopped licking for ICSS. LHA procainization suppressed both licking for juice and ICSS. Both intraperitoneal and intravenous 2-B4O stopped licking for juice and ICSS, but did not influence LHA responses to CTS1+ or CTS2+. The results suggest that dynamic interaction of AM-LHA-VTA are important for CTS+ learning, and 2-B4O acts directly on LHA neurons while maintaining afferent sensory inputs to the LHA.     

Characteristics of rat lateral hypothalamic neuron responses to smell and taste in emotional behavior

Single unit activity in the lateral hypothalamus (LHA) of the rat was recorded while the animal learned to discriminate cue signals. Normally preferred potables (glucose, orange, or grape solution) or intracranial self-stimulation (ICSS) were used as rewards. Electric shock or tail pinch were used as aversive stimuli. The same behavior, licking, was the response required to either obtain the rewarding stimuli or avoid the aversive ones. For positive reinforcement a rat was rewarded with fluid or ICSS upon licking a spout presented in front of its mouth. In negative reinforcement experiments, an aversive stimulus, electric shock or tail pinch, was applied if the rat did not lick the spout. Solutions having smell only, taste only, or smell-plus-taste, were prepared from oranges or grape extract. Of 392 neurons analyzed, 256 responded differentially to rewarding and aversive stimuli, and 138 of these were tested with the 3 different solutions. Similar LHA neural responses occurred during actual drinking of the 3 kinds of solutions, as well as on recognition of the cue signal. Responses to smell only had shorter latency than responses to taste only. Neural activity in response to solutions that could be both smelled and tasted was the sum of activity in response to taste-only solutions plus that in response to smell-only solutions. Cue signal responses were rapidly acquired, usually within 2-5 trials, for both taste-only and smell-only solutions. The results indicate the integration of both taste and olfactory information by the same LHA neurons, and these neurons are involved in cue signal learning. Present results of LHA neuronal responses to taste and smell suggest that the intensity of gustation and olfaction may add together to enhance instinctive hedonic sensations. These neurons are involved in the formation of stimulus-reinforcement association in learning, and in elicitation of conditioned emotional responses.     

Visual responses related to food discrimination in monkey lateral hypothalamus during operant feeding behavior

Single neuron activity was recorded from monkey lateral hypothalamic area (LHA) to relate neuronal events to food discrimination and initiation of procurement movement in operant bar press feeding behavior. Of 429 neurons tested, 68 (16%) responded during visual phase. Of these, 30 (7%) responded selectively to the sight of food or non-food associated with a juice reward, but not to the sight of meaningless non-food or food associated with aversive saline. Neuronal activity related to discrimination was readily influenced by extinction, reversal or satiation. The strength of visual responses was correlated with latency of bar press initiation and speed of bar pressing, but was not related directly to bar press movement. These suggest that the LHA is deeply involved in discrimination of reinforcement or non-reinforcement, and might be associated with higher functions to regulate internal states such as physiological need to get food during operant feeding behavior.     

Internal and external information processing by lateral hypothalamic glucose-sensitive and insensitive neurons during bar press feeding in the monkey

Single neuron activities in the lateral hypothalamic area (LHA) were recorded during bar press feeding task in the monkey. First registered neurons were sorted into 2 groups, glucose-sensitive (GS) and glucose-insensitive (GIS) neurons, depending on their glucose sensitivity. Then firing variations to feeding, electrophoretically applied catecholamines and opiate, and to odor and taste stimuli were investigated. GS neurons responded to dopamine, noradrenaline and morphine more often than GIS neurons. In feeding task GS neurons responded during bar press (BP) and reward (RW) periods with long-lasting inhibition of firing and at cue tone (CT) with transient inhibition, while GIS neurons responded during BP and RW periods mainly with excitation and at cue light (CL) with excitation. A majority of GS neurons responded to both odor and taste stimuli more often than GIS neurons. Data suggest that these two kinds of neurons in the LHA may be involved in different functional aspects of feeding: GS neurons, mainly in internal information processing and reward mechanism, and GIS neurons, in external information processing and motor aspects.     

Integrated lateral hypothalamic neural responses to natural and artificial rewards and cue signals in the rat

Effects of natural and intracranial electrical rewarding stimuli and cue signals were investigated while recording from single neurons in the rat lateral hypothalamus. The rat obtained both rewards using identical behavior, viz. licking. When both rewarding stimuli influenced a neuron, the responses were usually similar, i.e. both excitatory or both inhibitory. Only neurons that responded to either or both rewards acquired responses to tone cues, and these acquired responses were in the same direction as reward responses. The data indicate that the same single neuron in the lateral hypothalamus might be implicated in reward processes and learning.     

Neuronal responses in monkey lateral hypothalamus during operant feeding behavior

Single neuron activity was recorded from monkey lateral hypothalamus to investigate neuronal events correlated with operant bar press feeding behavior. The behavioral paradigm was divided into three phase: visual (discrimination), bar press (procurement), and ingestion (consummatory). Of 669 neurons tested, 158 (24%) responded in one or more phases. During the visual phase, 106 neurons (16%) responded. Of 80 neurons that responded in the visual phase and were tested systematically, 33 (41%, 33/80) responded selectively to the sight of food or nonfood objects associated with a juice reward, but not to the sight of nonfood or objects associated with aversive saline. Neuronal activity related to discrimination was modulated by satiation and learning (i.e., acquisition and extinction). During the bar press phase, 51 neurons (7.6%) responded. These responded tonically during the early or late stage of the bar press period, but did not depend on individual bar pressing motions. During ingestion, 90 neurons (13%) responded. The ingestion response was modulated by palatability of food and satiation. Data suggest that the LHA is deeply involved in operant feeding behavior; discrimination of food, drive to get food, and perception of reward, all of which are affected by learning and internal states such as hunger and satiety.     

Neural correlates to both emotion and cognitive functions in the monkey amygdala

Recent lesion and non-invasive studies identify the medial temporal lobe, including the amygdala, not only with emotion but also with working memory in relation to the prefrontal cortex. In the present study, amygdalar neuronal activity was recorded from monkeys during performance of discrimination tasks that led to presentation of emotion-related (rewarding or aversive) stimuli. The task had three phases: (1) discrimination (visual, auditory), (2) operant response (bar pressing) and (3) ingestion (reward) or avoidance (aversion). These neurons were further analyzed by a short-term memory task, delayed pair comparison (DPC) using colored lamps. Of 585 amygdalar neurons, 107 responded primarily to single sensory stimulation (40 vision related, 26 audition related, 41 ingestion related), 117 to multimodal stimulation (multimodal) and 14 responded selectively to only one item (selective). Of 417 neurons tested by the DPC, 122 responded in one or more phases. Of these 122 neurons, 10.7% responded in the delay period. These delay-responsive neurons also responded to various objects with positive and negative affective significance. These results suggest that amygdalar neurons are not specifically related to working memory, as are those in the inferotemporal and prefrontal cortices, but are related to more general non-specific functions or processes such as arousal or attention during the cognitive tasks. A functional role of the amygdala in working memory is discussed in terms of recent non-invasive studies suggesting a functional coupling between the amygdala and prefrontal cortex.     

Dopamine: the salient issue

There is general agreement that midbrain dopamine neurons play key roles in reward processing. What is more controversial is the role they play in processing salient stimuli that are not rewarding. This controversy has arisen for three main reasons. First, salient sensory stimuli such as tones and lights, which are assumed not to be rewarding, increase dopamine neuron activity. Second, aversive stimuli increase firing in a minority of putative dopamine neurons. Third, dopamine release is increased following aversive stimuli. Consequently, it has been suggested that these midbrain dopamine neurons are activated by all salient stimuli, rather than specifically by rewards. However, reconsideration of these issues, in light of new findings, suggests this controversy can be resolved in favour of reward theories.     

Tonically active neurons in the striatum encode motivational contexts of action

In order to achieve a goal, one procures immediately available rewards, escape from aversive events or endures absence of rewards. The neuronal substrate for these goal-directed actions includes the limbic system and the basal ganglia. In the basal ganglia, classes of projection neurons in the striatum show activity with motivational as well as sensorimotor properties, such as expectation of reward and task schedule for obtaining reward. Tonically active neurons (TANs), presumed cholinergic interneurons in the striatum, respond to reward-associated stimuli, evolve their activity through learning and respond also to aversive event-associated stimuli such as airpuff on the face. A recent study showed that responses to visual cues are less selective to whether the cue instructs reward or no reward. To address this paradox, we asked macaque monkeys to perform a set of visual reaction time tasks while expecting the reward, aversive event or absence of reward. We found that TANs respond to instruction stimuli associated with motivational outcomes but not to unassociated ones, and that they mostly differentiate associated instructions. We also found that the higher percentage of TANs in the caudate nucleus respond to stimuli associated with motivational outcomes than in the putamen, whereas the higher percentage of TANs in the putamen respond to GO signals than in the caudate nucleus especially for an action anticipating a reward. These findings suggest a distinct, pivotal role played by TANs in the caudate nucleus and putamen in encoding instructed motivational contexts for goal-directed action selection and learning in the striatum.     

Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rat

The effects of glucose injection into the hepatic portal vein on neural activity of the lateral hypothalamic area (LHA) were studied in rats. A majority of identified glucose-sensitive neurons in the LHA were inhibited by portal injection of glucose. This was found to be mediated through the alpha-noradrenergic pathways. Most of the glucose-insensitive neurons did not respond to the same procedure. Portal injection of hypertonic saline increased neural activity of some glucose-insensitive neurons but no glucose-sensitive neurons responded. Convergence of hepatic vagal afferent glucose-sensitive units on LHA glucose-sensitive neurons was clarified by this study.     

Glutamatergic Ventral Pallidal Neurons Modulate Activity of the Habenula–Tegmental Circuitry and Constrain Reward Seeking

Background

The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking.

Catecholaminergic mechanisms of feeding-related lateral hypothalamic activity in the monkey

The functional role of the catecholaminergic mechanism in the lateral hypothalamus (LHA), in feeding behavior of the monkey was investigated by single neuron activity recording and electrophoretic application of dopamine (DA), noradrenaline (NA) and their antagonists. The feeding paradigm had 4 phases: cue light (CL) signaled start of bar press; bar press (BP, 20-30 times); short cue tone (CT) triggered by last bar press signaled presentation of food; and ingestion-reward (RW). Of 312 neurons tested, 189 (61%) responded in one or more phases of the feeding task. Two types of response were observed: CL- or CT-related transient, and BP- or RW-related long-lasting responses. These feeding-related responses depended on the nature of the food and on the hunger-satiety level. DA excited or inhibited different neurons, while NA mainly inhibited firing. DA-sensitive neurons responded more often in the feeding task than insensitive neurons due mainly to differences in responsiveness to CL on (chi 2 test, P less than 0.01), at motor initiation, and during BP (P less than 0.05). Spiperone blocked the former two responses. NA-sensitive neurons responded more often in the feeding task due to responsiveness during BP and RW (P less than 0.01). Sotalol blocked some BP-related responses, and phenoxybenzamine and sotalol blocked the CT-related responses. The data suggest that dopaminergic and noradrenergic inputs in the LHA are crucial in task initiation and reward processing, respectively. Integration of these catecholaminergic and other inputs in the LHA might be important in accomplishing motivated feeding.     

Behavioral significance of monkey hypothalamic glucose-sensitive neurons

Feeding-related neuronal activity of lateral hypothalamic glucose-sensitive and glucose-insensitive neurons was investigated in behaving monkeys. The behavioral paradigm was a high fixed ratio of bar pressing for food reward signaled by light and tone cues. Twenty-seven percent of the neurons tested were glucose-sensitive. The population of neurons which changed in firing rate during the feeding task was higher among glucose-sensitive cells than among glucose-insensitive cells. The activity of many glucose-sensitive neurons decreased during the bar pressing and reward periods. A small population of glucose-sensitive neurons responded to cue stimuli. The results suggest that glucose-sensitive neurons are mainly involved in the drive and/or reward mechanism of feeding behavior, and that these cells may have specific roles in neural control of hunger-motivated food acquisition.     

Response properties of lateral hypothalamic neurons during ingestive behavior with special reference to licking of various taste solutions

Activity of 58 single neurons in the lateral hypothalamic area (LHA) was recorded while Wistar male rats were drinking water and various taste solutions in a test box. A cue tone was presented before opening of a shutter for access to a drinking spout. Except 8 neurons which were non-responsive in the present experimental paradigm, 50 neurons were classified into 3 types according to their response properties: (1) 10 neurons changed their activity with arousal state or circadian rhythm, (2) 10 neurons responded to specific sensory stimuli, i.e. 2 were classified as taste-responsive neurons, which responded excitatory to sodium salts, 3 neurons responded to olfactory stimulation, 5 to somatosensory stimulation applied to the perioral region, and (3) the remaining 30 decreased their activity during licking of liquids regardless of their qualities. Besides this classification, activity of 28 of 58 LHA neurons was altered after onset of the cue tone (or before start of licking), i.e. 24 increased their activity (learned anticipatory response), and 3 modulated their tonic activity into burst discharges corresponding to sniffing, and 1 increased its activity in relation to stepping toward the drinking spout. These data suggest that about half of the LHA neurons increased their activity in anticipatory (searching or approaching) periods just before ingestion, and decreased activity in rewarding periods during ingestion of water or sapid solutions.     

Responses of striatal neurons in the behaving monkey. 1. Head of the caudate nucleus

The activity of 394 neurons in the head of the caudate nucleus and the most anterior part of the putamen was analyzed in 3 behaving rhesus monkeys in order to analyze the functions of this part of the striatum. Of these neurons, 64.2% responded in the tests used in relation to, for example, environmental events, movements made by the monkey, the performance of a visual discrimination, or during feeding. However, only relatively small proportions of these neurons had responses which were unconditionally related to visual (9.6%), auditory (3.5%), or gustatory (0.5%) stimuli, or to movements (4.1%). Instead, the majority of the responsive neurons had activity in relation to stimuli or movements which was conditional, in that the responses occurred in only some test situations, and were often dependent on the performance of a task by the monkeys. Thus, it was found in the visual discrimination task that 14.5% of the neurons responded during a 0.5 sec tone/light cue period which signalled the start of each trial; 31.1% responded in the period in which the discriminative visual stimuli were shown, with 24.3% of these responding more to either the visual stimulus which signified food reward or to that which signified punishment; and 6.2% responded in relation to lick responses. Yet these neurons typically did not respond in relation to the cue stimuli, to the visual stimuli, or to movements, when these occurred independently of the task, or when performance of the task was prevented. Comparably, of the neurons tested during feeding, 25.8% responded when the food was seen by the monkey, 6.2% when he tasted it, and 22.4% during a cue given by the experimenter that a food or non-food object was about to be presented. However, only few of these neurons had responses to the same stimuli presented in different situations.It is concluded that many neurons in the head of the caudate nucleus and the most anterior part of the putamen respond in relation to events which are used as cues to prepare for the performance of tasks, including feeding, in which movements must be initiated. Other neurons respond in relation to the stimuli used and the movements made in these tasks. However, the majority of these neurons do not have unconditional sensory or motor responses. It is therefore suggested that the anterior neostriatum contains neuronal mechanisms which are important in the process by which environmental cues are used in the preparation of behavioral responses, and in the initiation of particular behavioral responses made in particular situations to particular environmental stimuli. Deficits in the initiation of movements following damage to striatal pathways may arise in part because of interference with these functions of the anterior neostriatum.     

Entopeduncular Nucleus Projections to the Lateral Habenula Contribute to Cocaine Avoidance

The aversive properties associated with drugs of abuse influence both the development of addiction and relapse. Cocaine produces strong aversive effects after rewarding effects wear off, accompanied by increased firing in the lateral habenula (LHb) that contributes to downstream activation of the rostromedial tegmental nucleus (RMTg). However, the sources of this LHb activation are unknown, as the LHb receives many excitatory inputs whose contributions to cocaine aversion remain uncharacterized. Using cFos activation and in vivo electrophysiology in male rats, we demonstrated that the rostral entopeduncular nucleus (rEPN) was the most responsive region to cocaine among LHb afferents examined and that single cocaine infusions induced biphasic responses in rEPN neurons, with inhibition during cocaine''s initial rewarding phase transitioning to excitation during cocaine''s delayed aversive phase. Furthermore, rEPN lesions reduced cocaine-induced cFos activation by 2-fold in the LHb and by a smaller proportion in the RMTg, while inactivation of the rEPN or the rEPN-LHb pathway attenuated cocaine avoidance behaviors measured by an operant runway task and by conditioned place aversion (CPA). These data show an essential but not exclusive role of rEPN and its projections to the LHb in processing the aversive effects of cocaine, which could serve as a novel target for addiction vulnerability.SIGNIFICANCE STATEMENT Cocaine produces well-known rewarding effects but also strong aversive effects that influence addiction propensity, but whose mechanisms are poorly understood. We had previously reported that the lateral habenula (LHb) is activated by cocaine and contributes to cocaine''s aversive effects, and the current findings show that the rostral entopeduncular nucleus (rEPN) is a major contributor to this LHb activation and to conditioned avoidance of cocaine. These findings show a critical, though not exclusive, rEPN role in cocaine''s aversive effects, and shed light on the development of addiction.     

Disturbance of approach‐avoidance behaviors in non‐human primates by stimulation of the limbic territories of basal ganglia and anterior insula

The basal ganglia (BG) are involved in motivation and goal‐directed behavior. Recent studies suggest that limbic territories of BG not only support reward seeking (appetitive approach) but also the encoding of aversive conditioned stimuli (CS) and the production of aversive‐related behaviors (avoidance or escape). This study aimed to identify inside two BG nuclei, the striatum and pallidum, the territories involved in aversive behaviors and to compare the effects of stimulating these territories to those resulting from stimulation of the anterior Insula (aIns), a region that is well‐known to be involved in aversive encoding and associated behaviors. Two monkeys performed an approach/avoidance task in which they had to choose a behavior (approach or avoidance) in an appetitive (reward) or aversive (air‐puff) context. During this task, either one (single‐cue) or two (dual‐cue) CS provided essential information about which context‐adapted behavior should be selected. Microstimulation was applied during the CS presentation. Stimulation generally reduced approaches in the appetitive contexts and increased escape behaviors (premature responses) and/or passive avoidance (noninitiated action) in aversive context. These effects were more pronounced in ventral parts of all examined structures, with significant differences observed between stimulated structures. Thresholds to induce effects were lowest in the pallidum. Striatal stimulation led to the largest diversity of effects, with a subregion even leading to enhanced active avoidance. Finally, aIns stimulations produced stronger effects in the dual‐cue context. These results provide causal evidence that limbic territories of BG, like aIns, play crucial roles in the selection of context‐motivated behaviors.     

Lateral parabrachial nucleus lesions in the rat: aversive and appetitive gustatory conditioning

Previous research involving tests of innate preferences and aversions shows that bilateral ibotenic acid lesions of the visceral neurons located in the lateral parabrachial nucleus of the pons selectively disrupt consumption of those gustatory stimuli whose intake is augmented or restricted by their postoral consequences. The present study examined the performance of the same experimental subjects in learned preference and aversion tasks. The lesioned rats failed to develop a conditioned taste aversion (Experiment 1), a conditioned flavor preference (Experiment 2), and a conditioned aversion to the oral trigeminal stimulus, capsaicin (Experiment 3). The pattern of results from both types of taste-guided behaviors (innate and learned) suggests that excitotoxic lesions of the lateral parabrachial nucleus diminish sensitivity to gastrointestinal feedback which, in the present experiments, precludes aversive and appetitive associative learning.     

Rapid and preferential activation of Fos protein in hypocretin/orexin neurons following the reversal of dehydration-anorexia

Dehydration (DE)-anorexia is stimulated by chronic consumption of hypertonic saline. Spontaneous nocturnal food intake is markedly reduced with this treatment but is rapidly reversed upon the return of drinking water. Here we examined the neurons in the lateral hypothalamic area (LHA) of chronically dehydrated rats for their peptidergic phenotype, colocalization, and activation profiles following the rapid reversal of anorexia. To do this, we used double-labeling combinations of Fos immunocytochemistry and radioisotopic- and digoxigenin-labeled in situ hybridization. We found that lateral hypothalamic corticotropin-releasing hormone (CRH) neurons show extensive coexpression with neurotensin mRNA, but they are distinct from hypocretin/orexin and melanin-concentrating hormone (MCH) neurons. Chronic dehydration increases Fos-ir in large numbers of neurons in dorsal regions of the LHA. Some of these LHA neurons also show increased CRH, but not hypocretin/orexin or MCH gene expression, as dehydration-anorexia develops. Furthermore, the behavioral sequence of eating and increased activity exhibited by DE animals in the minutes following water drinking is accompanied by a further increase in the number of Fos-ir nuclei in the LHA. Increased Fos activation occurs in a significant number of LHA hypocretin/orexin neurons, but not CRH or MCH neurons, in the LHA. Together these data implicate CRH but not hypocretin/orexin or MCH neurons in the LHA in the motor events associated with dehydration. However, when water is returned, contributions to the network controlling responses evidently come from hypocretin/orexin, but not CRH or MCH, neurons in the LHA.