Reinforcing Brain Stimulation Research Articles

Rodent Arena Tracker (RAT): A Machine Vision Rodent Tracking Camera and Closed Loop Control System.

Video tracking is an essential tool in rodent research. Here, we demonstrate a machine vision rodent tracking camera based on a low-cost, open-source, machine vision camera, the OpenMV Cam M7. We call our device the rodent arena tracker (RAT), and it is a pocket-sized machine vision-based position tracker. The RAT does not require a tethered computer to operate and costs about $120 per device to build. These features make the RAT scalable to large installations and accessible to research institutions and educational settings where budgets may be limited. The RAT processes incoming video in real-time at 15 Hz and saves x and y positional information to an onboard microSD card. The RAT also provides a programmable multi-function input/output pin that can be used for controlling other equipment, transmitting tracking information in real time, or receiving data from other devices. Finally, the RAT includes a real-time clock (RTC) for accurate time stamping of data files. Real-time image processing averts the need to save video, greatly reducing storage, data handling, and communication requirements. To demonstrate the capabilities of the RAT, we performed three validation studies: (1) a 4-d experiment measuring circadian activity patterns; (2) logging of mouse positional information alongside status information from a pellet dispensing device; and (3) control of an optogenetic stimulation system for a real-time place preference (RTPP) brain stimulation reinforcement study. Our design files, build instructions, and code for the RAT implementation are open source and freely available online to facilitate dissemination and further development of the RAT.

Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters.

Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (−60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release.

Operant tempo varies with reinforcement rate: implications for measurement of reward efficacy

Herrnstein's melioration theory has been used to account for the hyperbolic form of the single operant matching law and to scale the effectiveness of reinforcing brain stimulation. Underlying this scaling method is the assumption that the mean rate of responding during operant bouts (the response ‘tempo’) is fixed and does not vary with the rate of reinforcement. The validity of this account was assessed by testing the constant-tempo assumption via a survivor analysis of the distributions of inter-response times at different variable-intervals (VIs) in rats responding for rewarding electrical stimulation of the lateral hypothalamus. Contrary to the constant-tempo assumption, response tempo was not fixed but rather decreased as the VI was lengthened. This demonstration challenges Herrnstein's account of single-operant matching and suggests that the reinforcement rate that supports a half-maximal rate of responding on a single VI schedule may not provide a valid scale for the value of brain stimulation. Possible remedies are discussed. Although the conclusions of the study are restricted to experiments on brain stimulation reward in rats, the inter-response time analysis employed can provide the basis for testing the validity of the constant-tempo assumption in other species and for other reinforcers.

Hippocampal place cells can develop distinct representations of two visually identical environments.

The pattern separation ability of hippocampal place cells was tested in an environment in which two visually identical rectangular compartments (Box A and Box B) were connected by a hidden door. Small ensembles of neurons were recorded with tetrodes while the rat searched for randomly distributed loci for reinforcing brain stimulation. The first recording session in Box A was conducted after the rat had explored the environment for the first time for 30 min. Immediately thereafter, a hidden door between Box A and Box B was opened to let the rat into the unexplored compartment, and a 5-min recording session was run with the door concealed. A rearrangement of place fields in Box B was observed in 18/20 neurons and in 5/6 ensembles. Most place fields did not change between two successive sessions in Box B. When the rat returned to Box A, the ensembles of neurons were as likely to adopt the original Box A firing field pattern as the more recent Box B pattern. In order to control for the influence of extra-arena cues, the rat was gradually lifted in a closed bucket from Box A into Box B while the whole arena was rotated by 90 degrees. All but one neuron and all the ensembles followed the intra-arena cues. Both rotated Box B and Box A firing field patterns were represented but Box B pattern was stronger among the neuronal ensembles. These findings indicate that hippocampal place cells not only can develop distinct representations of two visually identical environments but also can selectively reactivate either one of these representations depending on the rat's recent experience.

N-methyl-D-aspartate lesions of the pedunculopontine nucleus block acquisition and impair maintenance of responding reinforced with brain stimulation.

Excitotoxin lesions of the pedunculopontine tegmental nucleus have been found to block the acquisition of a conditioned place preference induced by morphine or amphetamine, and it has been suggested that such lesions may attenuate the primary reinforcing effects of these drugs and, possibly, other reinforcers. The present study examined the effects of pedunculopontine lesions on the reinforcing effects of brain stimulation. N-methyl-D-aspartate-induced lesions of the pedunculopontine nucleus prevented spontaneous acquisition of lever pressing for brain stimulation reinforcement during five daily 1 h sessions of training. The effective lesions damaged the retrorubral fields in addition to the pedunculopontine tegmental nucleus. N-methyl-D-aspartate (25 or 50 nmol) lesions of the retrorubral fields did not block acquisition of self-stimulation, however, controls reached their maximum rate of responding in the first session, responding of rats with retrorubral field lesions gradually increased over five days. When excitotoxin-induced lesions of the pedunculopontine nucleus were made after acquisition of self-stimulation, lesioned rats continued to respond to brain stimulation, but at a lower rate than controls. The results show that pedunculopontine lesions interfere with the learning and expression of a response reinforced by brain stimulation just as they block learning motivated by drugs and natural rewards. They also suggest that collateral damage to the retrorubral fields may contribute to the effects of pedunculopontine lesions on reinforced behaviour. These data support the view that the pedunculopontine tegmental nucleus is involved in the process by which reinforcers control purposive behaviour.

Naltrindole, a δ-opioid antagonist, blocks MDMA's ability to enhance pressing for rewarding brain stimulation

Twelve rats were each fixed with a chronically indwelling bipolar electrode for stimulation of the medial forebrain bundle as it courses through the hypothalamus. These rats were trained to press a bar for intracranial stimulation of 0.3-s trains of 60 Hz sine waves for 10 min daily at three intensities. One intensity was just above threshold for maintaining pressing, one intensity was a high intensity that sustained considerable pressing, but not maximum pressing, and the other was intermediate to the others. After stable rates of pressing were obtained, rats received MDMA daily. MDMA significantly increased rates of pressing. Prior to a day when rats received MDMA, they also received an injection of naltrindole, a selective δ-opioid receptor antagonist. Naltrindole blocked MDMA's enhancement of pressing for reinforcing brain stimulation.

Effects of intracranial self-stimulation on selected physiological variables in rats

The purpose of this investigation was to characterize selected metabolic, cardiovascular, and hormonal responses to reinforcing intracranial self-stimulation (ICSS) of the ventral tegmental area (VTA) in rats. Twenty male Sprague-Dawley rats were stereotaxically implanted with bipolar electrodes aimed at the VTA of the brain. Rats were trained to lever-press for ICSS for 1 wk. While they adapted to the experimental environment by sitting in a metabolic operant chamber, they were connected to the electrode cable but did not lever-press. All animals were instrumented with arterial catheters. Rats receiving contingent stimulation (C-St; n = 10) performed 30 min of lever pressing in the metabolic operant chamber for reinforcing brain stimulation. Oxygen consumption (VO2), heart rate (HR), mean arterial pressure (MAP), and rectal temperature (Trec) increased with the onset and continuation of contingent brain stimulation over 30 min (P < 0.05). In addition, plasma norepinephrine (NE), epinephrine (Epi), and corticosterone increased significantly above resting values in C-St rats (P < 0.05). Five animals received investigator-delivered reinforcing brain stimulation (noncontingent stimulation; NC-St), with MAP, HR, VO2, NE, and Epi increasing significantly above resting values (P < 0.05). Trec and corticosterone were not responsive to noncontingent brain stimulation. With the exception of HR, nonstimulated controls (n = 5) did not experience increases above resting values in any of the variables measured. The responses suggest that contingent brain stimulation reward elicits heightened sympathetic arousal.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptor subtypes in opioid and stimulant reward.

Studies of the behaviourally-reinforcing actions of opioid and stimulant drugs of abuse are reviewed in an attempt to identify their reward-related brain receptors. We focus on data generated by drug self-administration, brain stimulation reinforcement, and conditioned place preference paradigms. A consistent body of evidence supports a role for mu and delta, but not kappa, receptors in opioid reward. Stimulant reward apparently involves both D1 and D2 receptors; the data favour D2 mediation of stimulant drug reinforcement with a permissive or modulatory role for D1 receptors. The reward-relevant opioid and dopamine receptors, as well as the cannabinoid (marijuana) receptor, share the ability to couple Gi proteins that mediate inhibition of adenylate cyclase and stimulation of K+ conductance. These signal transduction mechanisms thus may be generally implicated in the reinforcing properties of diverse drugs of abuse.

ECONOMIC SUBSTITUTABILITY OF ELECTRICAL BRAIN STIMULATION, FOOD, AND WATER

Concurrent variable-ratio schedules of electrical brain stimulation, food, and water were paired in various combinations as reinforcement of rats' lever presses. Relative prices of the concurrent reinforcers were varied by changing the ratio of the response requirements on the two levers. Economic substitutability, measured by the sensitivity of response ratio to changes in relative price, was highest with brain stimulation reinforcement of presses on both levers and lowest with food reinforcement of presses on one lever and water reinforcement of presses on the other. Substitutability with brain stimulation reinforcement of presses on one lever and either food or water reinforcement for presses on the other was about as high as with brain stimulation for presses on both levers. Electrical brain stimulation for rats may thus serve as an economic substitute for two reinforcers, neither of which is substitutable for the other.

Measuring threshold of reinforcing brain stimulation by the method of constant stimuli

A new method for measuring threshold of reinforcing electrical brain stimulation is described and results of a parametric study using this method are presented. Two groups of rats were trained under a concurrent FR-CRF (fixed ratio-continuous reinforcement) schedule of reinforcement provided by electrical stimulation of the lateral hypothalamus. The invariant intermittent FR schedule of reinforcement was used to maintain a baseline of behavior while a superimposed concurrent CRF schedule was used to measure reinforcement magnitude by varying the intensity of the CRF stimulus between zero and a maximum. Increasing and decreasing stimulus intensity on the CRF schedule leads to a gradual disappearance, respectively reappearance, of post-reinforcement pauses (PRPs) on the concurrent FR schedule, providing a criterion for changeover in schedule control, and thus, for threshold of reinforcement. To illustrate the measurement of threshold according to psychophysical requirements of the Method of Constant Stimuli, different CRF intensities were given in a randomized order. In one group of animals FR and CRF stimuli were given through the same electrode. Another group received FR and CRF stimuli through separate electrodes implanted in different hemispheres of the brain. For both groups the duration of the PRP was used as the dependent variable. The data of both groups showed a high negative correlation between the intensity of the CRF stimulus and the duration of the PRP, which is consistent with the results of experiments in which a Method of Limits procedure was used. On the basis of this relationship between CRF current intensity and PRP duration a threshold for reinforcing brain stimulation was calculated.

Morphine and diprenorphine together potentiate responding for positively reinforcing brain stimulation

Rats fixed with chronically indwelling bipolar electrodes for stimulation of the lateral hypothalamus were trained to press for brain stimulation. Subsequent to training, they were allowed to press for 30 min a day for a moderate intensity of stimulation until response rates stabilized. Then, prior to some opportunities to press, the rats were given either a 10-mg/kg dose of morphine sulfate or a 30-μg/kg dose of diprenorphine (an antagonist of morphine’s analgesia and behavioral suppression), or both. The large dose of morphine suppressed responding, and the small dose of diprenorphine facilitated responding, replicating previous observations. Morphine plus diprenorphine produced marked increments in pressing. These data provide further support for the idea that morphine’s capacity to facilitate responding for brain stimulation is unrelated to its analgesic properties. Also, the data support the idea of a separate opioid receptor for opioid reward.

Hedonic reactivity to sucrose in rats: Modification by pimozide

Reward summation functions (RSFs) are an important way to dissociate and quantify hedonic and motor effects of neuroleptics. Previously used only with brain stimulation reinforcement, we demonstrate they will also work using sucrose solution reinforcement. Eighteen male rats were trained to lever press on a CRF schedule for 0.01 ml sucrose solution reinforcers of varying concentration (0.025, 0.05, 0.1, 0.3, 0.5, 0.7, 0.9, 1.1, 1.7, 2.3 M). Making the lever harder to press caused an increase in the asymptote of the function, demonstrating a motor effect. Quinine added to the solutions (0.05%) caused the function to shift right, demonstrating an hedonic effect. Rats injected with 0.2 mg/kg pimozide, a dopamine antagonist, then tested four hours later, showed a right shift in the function with no change in asymptote. Thus, at this dose pimozide affects hedonic and not motor substrates of the CNS. These data demonstrate the generalizability of the RSF method to reinforcers other than brain self-stimulation.

Reinforcement delay of one second severely impairs acquisition of brain self-stimulation

The effect of delayed reinforcement on the acquisition of lateral hypothalamic self-stimulation was investigated. Brain stimulation reinforcement minimizes cues associated with reinforcement delivery (secondary reinforcement) and, by eliminating consummatory responses, permits precise temporal control of the interval between the operant response and reinforcement. Different groups were trained in daily 1-h sessions for brain stimulation reinforcement at one of 4 delay intervals (1, 2, 3 or 6 s). Responses made during the delay interval were not reinforced and reset the delay timer. Control groups (IMMEDIATE) were reinforced immediately, but were required to space responses--according to a delayed reinforcement of low rates (DRL) schedule--for an interval corresponding to one of the delay of reinforcement intervals. The DRL schedule equalized opportunities for reinforcement and non-reinforcement. At all intervals, rats trained with delayed reinforcement had significantly lower bar-press rates than controls trained with immediate reinforcement under DRL. When reinforcement schedules were switched (DELAY groups now get IMMEDIATE and vice versa), response rates rapidly shifted to levels appropriate to the new schedule. The pre-switch results indicate that delays even as short as 1 s markedly impede the acquisition of self-stimulation behavior. The post-switch results suggest that delay of reinforcement, like stimulation intensity, may determine the strength of hypothalamic reinforcement and hence final levels of performance.

Self-stimulation in the brain stem after ipsilateral precollicular decerebration

Rats were tested for self-stimulation after unilateral removal of the entire forebrain anterior to the superior colliculus. The stimulating electrodes were situated in the peribrachial region, just lateral to the superior cerebellar peduncle. Of 27 animals tested, 8 still self-stimulated after ipsilateral decerebration. Self-stimulation was exhibited from as early as a few hours to as long as 119 days after decerebration. The results are discussed in the context of the search for neural elements that subserve reinforcing brain stimulation.

The use of two operants to examine the nature of pimozide-induced decreases in responding for brain stimulation

Although a number of researchers have suggested that the brain’s dopaminergic neurons mediate the behavioral effects of reinforcement, others have argued that many of the observed behavioral effects of blocking dopaminergic receptors can be attributed to motor deficits. To decide between these alternatives, rats were trained to leverpress and run in a wheel for brain stimulation reinforcement in daily two-session training periods. They then were tested with the dopamine receptor blocker, pimozide (1.0 mg/kg); rats receiving leverpress testing in both sessions responded significantly less in the second session than did rats tested on the sequence of wheel-lever. These results support the hypothesis that pimozide interferes with the reinforcement process rather than simply producing motor deficits.

Behavioral and dimensional contrast in rats.

Rats pressed a nose key for brain stimulation reinforcement presented on a fixed-interval schedule. Stimuli were drawn at random from a continuum of 12 white noise intensities in the range 62-95 decibels, spaced in 3 decibel steps. Experiment 1 varied the number of stimuli and the reinforcement contingencies associated with them. In Condition I (baseline) all stimuli signaled reinforcement; in Conditions II and III stimuli from one half of the continuum signaled reinforcement and those from the other half, extinction. However, in Condition II the 6 stimuli from the middle of the continuum were omitted. Experiment 2 held constant the number of stimuli and varied their spacing. In Condition I, each of 6 sounds signaled reinforcement. In Conditions II and II, three stimuli from one half of the continuum signaled reinforcement and three from the other half, extinction. However, in Condition II the stimuli were near the extremes of the continuum (Stimuli 1, 3, 4, 9, 10, 12). Condition III replaced Stimulus 3 with Stimulus 6 and Stimulus 10 with Stimulus 7. Behavioral contrast was seen in an increase over baseline in response rate to the stimuli associated with the constant schedule component when the variable component was changed to extinction. Dimensional contrast was seen in a further elevation of rate to intermediate positive stimulus values when stimuli were added to the border region between positive and negative values.

Reinforcement and the organization of behavior in golden hamsters: Brain stimulation reinforcement for seven action patterns.

Reinforcement and the organization of behavior in golden hamsters: Brain stimulation reinforcement for seven action patterns.

Reinforcement and the organization of behavior in golden hamsters: Brain stimulation reinforcement for seven action patterns.

Golden hamsters were reinforced with intracranial electrical stimulation of the lateral hypothalamus (ICS) for spending time engaging in one of seven topographically defined action patterns (APs). The stimulation used as reinforcer elicited hoarding and/or feeding and supported high rates of bar pressing. In Experiment 1, hamsters were reinforced successively for digging, open rearing, and face washing. Digging increased most in time spent, and face washing increased least. Experiments 2-5 examined these effects further and also showed that "scrabbling," like digging, was performed a large proportion of the time, almost without interruption, for contingent ICS but that scratching the body with a hindleg and scent-marking showed relatively little effect of contingent ICS, the latter even in an environment that facilitated marking. In Experiment 6, naive hamsters received ICS not contingent on behavior every 30 sec (fixed-time 30-sec schedule). Terminal behaviors that developed on this schedule were APs that were easy to reinforce in the other experiments, but a facultative behavior, face washing, was one not so readily reinforced. Experiment 7 confirmed a novel prediction from Experiment 6--that wall rearing, a terminal AP, would be performed at a high level for contingent ICS. All together, the results point to both motivational factors and associative factors being involved in the considerable differences in performance among different reinforced activities.

Response : Brain Stimulation Reinforcement: Implications of an Electrode Artifact

<i>Response</i> : Brain Stimulation Reinforcement: Implications of an Electrode Artifact

Brain Stimulation Reinforcement: Implications of an Electrode Artifact

Brain Stimulation Reinforcement: Implications of an Electrode Artifact