Brain reward circuitry: insights from unsensed incentives

The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.     

Opposite effects of cholecystokinin octapeptide (CCK-8) and tetrapeptide (CCK-4) after injection into the caudal part of the nucleus accumbens or into its rostral part and the cerebral ventricles

Neurons with colocalized cholecystokinin and dopamine are present predominantly in the ventral tegmental area and project mainly to the caudal part of the medial nucleus accumbens. The activity of this dopamine system can be evaluated by means of the intracranial self-stimulation behavior on male Wistar rats having chronic electrodes implanted into the medial forebrain bundle in the postero-lateral area of the hypothalamus. The direct injection of 150 pmol CCK-8 into the medio-caudal accumbens induced an increase of intracranial self stimulation while a similar administration into its rostral portion produced a slight decrease of intracranial self-stimulation. The administration of 300 pmol CCK-4 into the same medio-caudal part of the accumbens produced an inhibitory action on intracranial self stimulation lasting for 25 min. The injection of 70 to 1300 pmol CCK-4 into the cerebral ventricles produced no change on intracranial self-stimulation. The intracerebroventricular injection of 70 pmol CCK-8 induced a large decrease of intracranial self-stimulation lasting for 20 min. Sodium chloride 0.15 M or unsulphated CCK-8 injection were without effect in either case. These results support the ideas that intracerebroventricular CCK-8 injection inhibits accumbens dopaminergic activity but that CCK-8 injection into the medio-caudal part of the accumbens, where nerve terminals with colocalized CCK and DA are present, facilitates this dopaminergic activity. In addition at the level of medio-caudal accumbens, CCK-8 and CCK-4 have opposite effects.     

A behavioral version of catecholamine involvement in new learning rewarded by brain stimulation.

Numerous studies in the rat indicate that catecholamines (CA) mediate rewarding properties of self-administered electrical stimulation to the brain. One such property is the learning of new response-reinforcement relationships. In the present experiment, amphetamine which potentiates CA at the synapse produces stereotypical responding but does not interfere with the learning of new response-reinforcement relationships. Apomorphine, which mimics dopamine (DA) at DA receptors, also produces stereotypy and interferes with learning. The results suggest that DA released by stimulation mediates the stereotyped responding seen in intracranial self-stimulation (ICS) but norepinephrine mediates reward of newly learned responses.     

Interhemispheric relations of prefrontal cortical neurons in rats during emotional stimulation of increasing intensity

Unit activity of the prefrontal cortex of the right and left brain hemispheres of rats was recorded during intracranial stimulation of emotionally positive and negative brain structures. The neurons were divided according to their reaction to a change in food motivation: cells that decrease (M-neurons) and cells that increase their firing frequencies (R-neurons) after feeding. Three levels of stimulation current intensity were used. When stimuli of subthreshold intensity (evoking the behavioral reaction of smelling) were applied, the recorded neuronal activity was higher in the left hemisphere. During threshold emotionally positive or negative stimulation (producing approach behavior or freezing, respectively), activity of M-neurons was higher in the right hemisphere, whereas the left-side R-neurons were more active than the right-side ones. During strong emotionally positive stimulation producing self-stimulation, the firing frequency of both groups of neurons was higher in the left hemisphere. Strong emotionally negative stimulation that evoked behavioral avoidance to a greater extent activated the right hemisphere.     

Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis

Dopamine was measured by microdialysis in the nucleus accumbens of freely moving rats while they experienced rewarding food, brain stimulation and drugs. Extracellular dopamine increased 37% when the animals pressed a lever for food reward. Electrical stimulation of a lateral hypothalamic feeding-reward (self-stimulation) site caused a similar increase in dopamine, with or without food. At the site in the nucleus accumbens where rats will administer amphetamine to themselves, injections of amphetamine or cocaine increased extracellular dopamine five-fold. Thus amphetamine and cocaine increase dopamine in a behavior reinforcement system which is normally activated by eating. Conversely, the release of dopamine by eating could be a factor in addiction to food.     

Reinforcing stimulation of the postero-lateral hypothalamus and mating behaviour in the rat.

Male rats implanted with chronic electrodes into the postero-lateral hypothalamic site were tested for self-stimulation behaviour. Rats exhibiting steady self-stimulation behaviour were observed during mating tests with an oestrus female. During these tests the hypothalamus of male rats was stimulated. Results show that no stimulus-bound sexual behaviour was observed. Nevertheless, correlations were found between the rewarding value of the cerebral stimulation and the specific sexual components of mating behaviour. These results are interpreted with the hypothesis of a balancing effect between the reward elicited by direct stimulation of the brain and reward acquired by the presence of an oestrus female.     

Reward-related FMRI activation of dopaminergic midbrain is associated with enhanced hippocampus-dependent long-term memory formation

Long-term potentiation in the hippocampus can be enhanced and prolonged by dopaminergic inputs from midbrain structures such as the substantia nigra. This improved synaptic plasticity is hypothesized to be associated with better memory consolidation in the hippocampus. We used a condition that reliably elicits a dopaminergic response, reward anticipation, to study the relationship between activity of dopaminergic midbrain areas and hippocampal long-term memory in healthy adults. Pictures of object drawings that predicted monetary reward were associated with stronger fMRI activity in reward-related brain areas, including the substantia nigra, compared with non-reward-predicting pictures. Three weeks later, recollection and source memory were better for reward-predicting than for non-reward-predicting pictures. FMRI activity in the hippocampus and the midbrain was higher for reward-predicting pictures that were later recognized compared with later forgotten pictures. These data are consistent with the hypothesis that activation of dopaminergic midbrain regions enhances hippocampus-dependent memory formation, possibly by enhancing consolidation.     

Arterial blood pressure and heart rate changes during self-stimulation by dogs in the basal forebrain region, lateral preoptic area, hypothalamus, ventral midbrain and amygdala.

In dogs pressing a lever for a brain-stimulation reward, arterial blood pressure (ABP) was elevated for 20 out of 24 sites tested, but this effect was usually conspicuous only at twice the threshold current sustaining stable performance. Hypertension was seen only in one ventral tegmental and two hypothalamic sites. In three anterior placements the ABP and heart rate (HR) increased more upon a fixed ratio than on continuous reinforcement. In most sites, self-stimulation was accompanied by cardiac acceleration; however, in some placements the HR was similar to or even less than control values. Continuous stimulation (5-10 sec) at one nucleus accumbens and four hypothalamic sites by the experimenter was aversive and produced a clearcut pressor response. The cardiovascular changes seem to depend on a spread of current to brain centres controlling circulatory functions and also, to some extent, on the animal's motor activity. The results contradict the claim that a causal relationship exists between the autonomic concomitants of self-stimulation and the intrinsic nature of the brain-stimulation reward.     

Programs of Gene Expression During the Laying Down of Memory Formation as Revealed by DNA Microarrays

Many experiments in the past have demonstrated the requirement of de novo gene expression during memory formation. In contrast to the initial reductionistic view that genes relevant to learning and memory would be easily found and would provide a simple key to understand this brain function, it is becoming apparent that the genetic contribution to memory is complex. Previous approaches have been focused on individual genes or genetic pathways and failed to address the massively parallel nature of genome activities and collective behavior of the genes that ultimately control the molecular mechanisms underlying brain function. In view of the broad variety of genes and the cross talk of genetic pathways involved in this regulation, only gene expression profiles may reflect the complete behavior of regulatory pathways. In this review we illustrate how DNA microarray-based gene expression profiling may help to dissect and analyze the complex mechanisms involved in gene regulation during the acquisition and storage of memory in the mammalian brain.     

Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation

It has become increasingly important to assess mood states in laboratory animals. Tests that reflect reward, reduced ability to experience reward (anhedonia) and aversion (dysphoria) are in high demand because many psychiatric conditions that are currently intractable in humans (e.g., major depression, bipolar disorder, addiction) are characterized by dysregulated motivation. Intracranial self-stimulation (ICSS) can be utilized in rodents (rats, mice) to understand how pharmacological or molecular manipulations affect the function of brain reward systems. Although many different methodologies are possible, we will describe in this protocol the use of medial forebrain bundle (MFB) stimulation together with the 'curve-shift' variant of analysis. This combination is particularly powerful because it produces a highly reliable behavioral output that enables clear distinctions between the treatment effects on motivation and the treatment effects on the capability to perform the task.     

Enhancement of Declarative Memory: From Genetic Regulation to Non-invasive Stimulation

The problem of memory enhancement is extremely important in intellectual activity areas and therapy of different types of dementia, including Alzheimer’s disease (AD). The attempts to solve this problem have come from different research fields. In the first part of our review, we describe the results of targeting certain genes involved in memory-associated molecular pathways. The second part of the review is focused on the deep stimulation of brain structures that can slow down memory loss in AD. The third part describes the results of the use of non-invasive brain stimulation techniques for memory modulation, consolidation, and retrieval in healthy people and animal models. Integration of data from different research fields is essential for the development of efficient strategies for memory enhancement.     

Epigenetic memory: the Lamarckian brain

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level.     

Hypothalamic self-stimulation and stimulation escape in relation to feeding and mating.

This review begins with James Olds' discovery that self-stimulation at various brain sites can be influenced by food intake or androgen treatment. It then describes our research designed to reveal the functional significance of self-stimulation. The evidence suggests that lateral hypothalamic self-stimulation is controlled by many of the same factors that control feeding. We believe this control is exerted by at least two neural mechanisms. One is the classical, medial hypothalamic satiety system. Another is an adrenergic system ascending from the midbrain to the lateral hypothalamus. Damage to either one can disinhibit self-stimulation and feeding, thus contributing to obesity. Some of our studies use rats with two electrodes, one that induces feeding and one that induces mating. There are two response levers in the test cage, one for self-stimulation and one for escape from automatic stimulation. With the feeding electrode, rats self-stimulated less and escaped more after a meal than before. The same shift occurred after an anorectic dose of insulin or the commercial appetite suppressant phenylpropanolamine. With the sex electrode the shift from reward to aversion occurred after ejaculation. The review ends with credit to James Olds for pioneering this line of research into the neuropsychology of reinforcement.     

At What Stage of Neural Processing Does Cocaine Act to Boost Pursuit of Rewards?

Dopamine-containing neurons have been implicated in reward and decision making. One element of the supporting evidence is that cocaine, like other drugs that increase dopaminergic neurotransmission, powerfully potentiates reward seeking. We analyze this phenomenon from a novel perspective, introducing a new conceptual framework and new methodology for determining the stage(s) of neural processing at which drugs, lesions and physiological manipulations act to influence reward-seeking behavior. Cocaine strongly boosts the proclivity of rats to work for rewarding electrical brain stimulation. We show that the conventional conceptual framework and methods do not distinguish between three conflicting accounts of how the drug produces this effect: increased sensitivity of brain reward circuitry, increased gain, or decreased subjective reward costs. Sensitivity determines the stimulation strength required to produce a reward of a given intensity (a measure analogous to the KM of an enzyme) whereas gain determines the maximum intensity attainable (a measure analogous to the vmax of an enzyme-catalyzed reaction). To distinguish sensitivity changes from the other determinants, we measured and modeled reward seeking as a function of both stimulation strength and opportunity cost. The principal effect of cocaine was a two-fourfold increase in willingness to pay for the electrical reward, an effect consistent with increased gain or decreased subjective cost. This finding challenges the long-standing view that cocaine increases the sensitivity of brain reward circuitry. We discuss the implications of the results and the analytic approach for theories of how dopaminergic neurons and other diffuse modulatory brain systems contribute to reward pursuit, and we explore the implications of the conceptual framework for the study of natural rewards, drug reward, and mood.     

Performing Behavioral Tasks in Subjects with Intracranial Electrodes

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in different areas of their brain for the localization of their seizure focus and eloquent areas. After implantation, the patient must remain in the hospital until the pathological area of brain is found and possibly resected. During this time, these patients offer a unique opportunity to the research community because any number of behavioral paradigms can be performed to uncover the neural correlates that guide behavior. Here we present a method for recording brain activity from intracranial implants as subjects perform a behavioral task designed to assess decision-making and reward encoding. All electrophysiological data from the intracranial electrodes are recorded during the behavioral task, allowing for the examination of the many brain areas involved in a single function at time scales relevant to behavior. Moreover, and unlike animal studies, human patients can learn a wide variety of behavioral tasks quickly, allowing for the ability to perform more than one task in the same subject or for performing controls. Despite the many advantages of this technique for understanding human brain function, there are also methodological limitations that we discuss, including environmental factors, analgesic effects, time constraints and recordings from diseased tissue. This method may be easily implemented by any institution that performs intracranial assessments; providing the opportunity to directly examine human brain function during behavior.     

Kelatorphan,a potent enkephalinases inhibitor,presents opposite properties when injected intracerebroventricularly or into the nucleus accumbens on intracranial self-stimulation

The ventral tegmental area contains a high density of dopaminergic perikaryon which present ascending axonal projections notably to the nucleus accumbens. This system, referred as the mesolimbic dopamine system has been demonstrated to display moderate to high density of enkephalin-containing fibers. This topographical analogy led us to evaluate the properties of kelatorphan, a new potent inhibitor of multiple enkephalin-degrading enzymes, on this mesolimbic system.Intracranial self-stimulation behavior served to estimate this mesolimbic dopaminergic function.Kelatorphan was injected either into the lateral ventricle or into the nucleus accumbens. Kelatorphan elicited opposite behavioral profiles, i.e. an intracranial self-stimulation increase when intracerebroventricularly injected (70 nmol) and a decreased self-stimulation behavior when directly administered into the nucleus accumbens (35 nmol).The results thus suggest that kelatorphan which protects endogenous enkephalins against enzymatic degradation seemed to act on the regulation of the mesolimbic dopamine system.     

Thalamocortical dynamics of sleep: roles of purinergic neuromodulation

Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output.     

The restless brain: how intrinsic activity organizes brain function

Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain''s energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease.     

Long-term changes in self-stimulation threshold by repeated morphine and naloxone treatment

To analyse the interaction between endogenous opioid systems and brain reward, the influence of repeated treatment for 3 weeks with morphine and the opioid antagonist naloxone was investigated in rats with self-stimulation electrodes in the ventral tegmental area. Changes in threshold of self-stimulation determined by a response rate insensitive two lever method were considered as changes in reward. Morphine induced a temporary decrease of the response rate which lasted 3 days, and decreased the threshold for self-stimulation. The effect on threshold remained present till morphine treatment was discontinued, indicating that tolerance does not develop to this effect of morphine. Repeated naloxone treatment gradually increased the threshold for self-stimulation. This effect persisted after discontinuation of naloxone treatment. It is concluded that blockade of opioid receptors induces long term changes in the setpoint of self-stimulation reward.     

The effects of feeding and fasting on self-stimulation

The effects of ad libitum feeding and 72 hr fasting on intracranial electrical self-stimulation behaviour (ICSS) were tested in cats. In contrast to previous studies it was found that the opposite manipulations in food intake, i.e. ad libitum feeding fasting, often induced identical changes in lever-pressing rate even in cases of lateral hypothalamic self-stimulation. Both increase and decrease in lever-pressing rate for ICSS could be observed depending rather on the electrically elicited behaviours than the precise anatomical location of the stimulating electrodes. It is concluded that changes in ICSS induced by food intake and food deprivation are probably secondary to the changes in activity level.