Functional mapping of the prosencephalic systems involved in organizing predatory behavior in rats

The study of the neural basis of predatory behavior has been largely neglected over the recent years. Using an ethologically based approach, we presently delineate the prosencephalic systems mobilized during predation by examining Fos immunoreactivity in rats performing insect hunting. These results were further compared with those obtained from animals killed after the early nocturnal surge of food ingestion. First, predatory behavior was associated with a distinct Fos up-regulation in the ventrolateral caudoputamen at intermediate rostro-caudal levels, suggesting a possible candidate to organize the stereotyped sequence of actions seen during insect hunting. Insect predation also presented conspicuous mobilization of a neural network formed by a distinct amygdalar circuit (i.e. the postpiriform-transition area, the anterior part of cortical nucleus, anterior part of basomedial nucleus, posterior part of basolateral nucleus, and medial part of central nucleus) and affiliated sites in the bed nuclei of the stria terminalis (i.e. the rhomboid nucleus) and in the hypothalamus (i.e. the parasubthalamic nucleus). Accordingly, this network is likely to encode prey-related motivational values, such as prey’s odor and taste, and to influence autonomic and motor control accompanying predatory eating. Notably, regular food intake was also associated with a relatively weak Fos up-regulation in this network. However, during regular surge of food intake, we observed a much larger mobilization in hypothalamic sites related to the homeostatic control of eating, namely, the arcuate nucleus and autonomic parts of the paraventricular nucleus. Overall, the present findings suggest potential neural systems involved in integrating prey-related motivational values and in organizing the stereotyped sequences of action seen during predation. Moreover, the comparison with regular food intake contrasts putative neural mechanisms controlling predatory related eating vs. regular food intake.     

Cholinergic modulation of mesolimbic dopamine function and reward

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems.     

Dopamine,addiction and reward

The role of dopamine was inferred in reward processes from early studies showing that psychomotor stimulants such as cocaine and amphetamine could facilitate intracranial self-stimulation. Subsequent studies showed that dopamine-receptor antagonists could attenuate brain stimulation reward and completely block the reinforcing effects of cocaine and amphetamine as measured by direct intravenous self-administration of these drugs. A specific dopaminergic substrate for both the facilitation of brain stimulation reward and the self-administration of psychomotor stimulants appears to be the region of the nucleus accumbens in the forebrain. This structure receives significant limbic afferents and has significant projections to the extrapyramidal motor system. Chronic administration of cocaine and amphetamine seem to have the opposite effects to acute injections and during withdrawal lead to increases in brain stimulation reward thresholds and decreases in dopamine release in the nucleus accumbens. This same nucleus accumbens dopamine projection seems to be critical for the motor activation associated with the anticipation of both drug and non-drug rewards. These results suggest that drugs that activate the mesolimbic dopamine system have such powerful reinforcing effects because they facilitate the attentional-motor systems critical for approach behaviour and the behavioural activation associated with incentive-motivation.     

Cortical mechanisms of cocaine sensitization

Behavioral sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine. Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use. Much research has been conducted to determine the neural mechanisms of sensitization. The bulk of this effort has focused on the nucleus accumbens and ventral tegmental area (VTA) that comprise a portion of the mesolimbic dopamine system. Recently, studies have begun to also explore the role of the medial prefrontal cortex (mPFC) in sensitization, in part because this region provides glutamatergic innervation to the VTA and nucleus accumbens. The present review will coalesce these studies into a working hypothesis that states that cocaine sensitization results from a decrease in inhibitory modulation of excitatory transmission from the mPFC to the VTA and nucleus accumbens. The discussion will revolve around how repeated cocaine exposure alters dopamine, gamma-aminobutyric acid (GABA), and glutamate regulation of pyramidal cell activity. It will be proposed that cocaine-induced alterations in cortical transmission occur in two phases. During early withdrawal from repeated cocaine exposure, changes in neurotransmitter release are thought to underlie the decreased inhibitory modulation of pyramidal projection neurons. Following more prolonged withdrawal, the attenuation in inhibitory transmission appears to occur at the receptor level. A model will be presented that may serve to direct future studies on the involvement of the mPFC in the development of cocaine sensitization, which ultimately could lead to development of pharmacotherapies for cocaine addiction.     

海洛因依赖患者自然戒断状态下症状频谱的动态变化

目的 :了解自然戒断状态下不同时期戒断症状发生率的动态变化以及导致患者复吸的主要原因。方法 :对 15 8例强制戒毒病人 ,于戒断后 2 4小时 ,72小时 ,7天 ,10天 ,1月 ,3月进行戒断症状评定。结果 :急性期戒断症状以焦虑、渴求、失眠、疲乏、食欲减退、疼痛、出汗、流泪、流涕、呵欠等症状的发生频率为高 ,而急性脱瘾后恢复期则以渴求、失眠、疲乏、焦虑 ,性欲望减退、情绪抑郁等为主要表现。导致病人复吸的主要原因依次为心理渴求 ,回到吸毒朋友的社交圈 ,睡眠障碍、周身不适、焦虑不安、空虚无聊、情绪不佳等稽延性症状 ,及来自家庭社会的应激。结论 :海洛因依赖患者在不同的戒断时期症状表现有所不同 ,导致复吸的原因亦多种多样 ,提示在不同戒断时期 ,治疗和预防复吸的方法应有所不同 ,应加强可以人为干预因素的控制 ,减少复吸率。     

Dynamic changes in orbitofrontal neuronal activity in rats during opiate administration and withdrawal

The orbitofrontal cortex is involved in the reinforcing effects of drugs of abuse. However, how the dynamic activity in OFC changes during opiate administration and withdrawal period has not been investigated. We first tested the effects of opiates and drug craving with the conditioned place preference paradigm, using manganese-enhanced magnetic resonance imaging and traditional electroencephalograph recording techniques in rats. T1-weighted 2D MRI (4.7 T) was used after unilateral injection of MnCl(2) (200 nL, 80 mM) into the right orbitofrontal cortex. The manganese-enhanced magnetic resonance imaging data suggested that the OFC activity decreased during the opiate administration period but recovered increasingly during the withdrawal period. Also, we found decreases and increases in gamma-band (20-100 Hz) activity during the opiate administration and withdrawal period, respectively. Our results showed that orbitofrontal cortex activity decreased during morphine administration and then went up progressively over several days during withdrawal. The time course of the recovery of orbitofrontal activity from inhibition during the withdrawal period may be related to the experience of drug craving.     

The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies

Background

A growing number of functional magnetic resonance imaging (fMRI) studies have been conducted in major depressive disorder (MDD) to elucidate reward-related brain functions. The aim of this meta-analysis was to examine the common reward network in the MDD brain and to further distinguish the brain activation patterns between positive stimuli and monetary rewards as well as reward anticipation and outcome.

Methods

A series of activation likelihood estimation (ALE) meta-analyses were performed across 22 fMRI studies that examined reward-related processing, with a total of 341 MDD patients and 367 healthy controls.

Results

We observed several frontostriatal regions that participated in reward processing in MDD. The common reward network in MDD was characterized by decreased subcortical and limbic areas activity and an increased cortical response. In addition, the cerebellum, lingual gyrus, parahippocampal gyrus and fusiform gyrus preferentially responded to positive stimuli in MDD, while the insula, precuneus, cuneus, PFC and inferior parietal lobule selectively responded to monetary rewards. Our results indicated a reduced caudate response during both monetary anticipation and outcome stages as well as increased activation in the middle frontal gyrus and dorsal anterior cingulate during reward anticipation in MDD.

Limitations

The reward-related tasks and mood states of patients included in our analysis were heterogeneous.

Conclusions

Our current findings suggest that there exist emotional or motivational pathway dysfunctions in MDD during reward-related processing. Future studies may be strengthened by paying careful attention to the types of reward used as well as the different components of reward processing examined.     

A disposition to reappraise decreases anterior insula reactivity during anxious anticipation

Across individuals there is variability in one's inherent tendency to reappraise emotional events in everyday life, which may be related to how worried one becomes in the presence of an anticipated aversive event. The extent to which this natural tendency to reappraise has neurobiological correlates during anxious anticipation is unknown. Neuroimaging research indicates that responses in the anterior insula precede anticipated aversive events and appear to represent one's affective feeling state of anxious anticipation. Successful cognitive reappraisal should weaken this anticipatory insula response. Here, functional magnetic resonance images were acquired while participants completed an anticipation task. We found increased anterior insula activation during aversive anticipation and a negative association between anxious anticipatory right anterior insula reactivity and dispositional reappraisal. Thus, even without the instruction to reappraise, individuals high in dispositional reappraisal tended to have a reduced anticipatory insula response to aversive stimuli, thereby down-regulating a neural substrate for aversive anticipation.     

Activity and distribution of learning-related neurons in monkey (Macaca fuscata) prefrontal cortex

The involvement of monkey (Macaca fuscata) prefrontal cortex (PFC) neurons in motor output decisions was studied by recording single neuron activity during 3 tasks: (a) go-left, go-right, or no-go decisions, (b) operant bar press feeding based on discrimination of food and nonfood, and (c) either delayed matching-to-sample (DMS) or DMS with response delay. Combinations of single neuron responses during the 3 tasks suggested 7 types of PFC neurons that were related to attention, choice, task-unique memory, reward anticipation, laterality, initiation of movement, and suppression of movement. The authors suggest that responses of PFC neurons do not depend on physical properties of the stimuli, but on their behavioral significance. PFC neurons might be important for appropriate behavior in response to external stimuli and internal or motivational factors.     

Differences of photographs inducing craving between alcoholics and non-alcoholics

Many researchers have used cue reactivity paradigm to study alcohol craving. But the difference of craving response to drinks between alcoholic patients and social drinkers was little evaluated. To investigate characteristics of alcohol-related visual cues which induce alcohol craving in alcoholism, we examined the response of subjects to alcohol-related cues considering qualitative aspects. The authors developed 27 photographs related to alcohol as candidate visual cues. Thirty five patients with alcohol dependence, 35 heavy drinkers and 35 social drinkers were shown these pictures and asked to rate these 6 pictures in order of inducing alcohol craving the most. 'A glass of Soju' and 'A Party scene' were chosen as the alcohol-related visual cues which induced craving the most in the patients and heavy drinkers, respectively. The results suggest that the patients with alcohol dependence are more absorbed by alcohol without drinking context such as an atmosphere or situation involving drinking. Heavy drinkers may experience craving in anticipation of being in a drinking situation.     

Natural selective attention: orienting and emotion

The foundations of orienting and attention are hypothesized to stem from activation of defensive and appetitive motivational systems that evolved to protect and sustain the life of the individual. Motivational activation initiates a cascade of perceptual and motor processes that facilitate the selection of appropriate behavior. Among these are detection of significance, indexed by a late centro-parietal positivity in the event-related potential, enhanced perceptual processing, indexed by a initial cardiac deceleration, and preparation for action, indexed by electrodermal changes. Data exploring the role of stimulus novelty and significance in orienting are presented that indicate different components of the orienting response habituate at different rates. Taken together, it is suggested that orienting is mediated by activation of fundamental motivational systems that have evolved to support survival.     

Time-dependent change of ERK phosphorylation levels in the nucleus accumbens during withdrawals from repeated cocaine

Extracellular signal-regulated kinase (ERK) has been implicated in cocaine-induced behavioral sensitization. We sought to determine whether ERK activation in the nucleus accumbens (NAcc), the site mediating the expression of behavioral sensitization, shows time-dependent changes after cocaine withdrawals. The basal levels of ERK phosphorylation in the NAcc show no changes on withdrawal day 1, while they increase on day 7, then gradually lower down to reach the same level on day 21 in cocaine compared to saline pre-exposed rats. Either total ERK or both phosphorylated and total p38 protein levels are not different in any time-point measurements. These results suggest that such time-dependent ERK activation in the NAcc may contribute to neuronal plasticity leading to long-lasting behavioral changes such as drug craving.     

Event-related potential correlates of non-motor anticipation.

A slow negative shift called "stimulus-preceding negativity" (SPN) has been observed preceding feedback. The aim of the present study is to investigate whether the SPN is related to perceptual or conceptual anticipation. Event-related potentials (ERPs) were recorded in an S1-S2-S3 sequence with intervals of 3 s. S1 was an auditory warning signal; the task stimulus presented at S2 consisted of two digits on which subjects (n = 8) performed an arithmetic task. They had to match their solution with a probe stimulus presented at S3. Perceptual anticipation was manipulated by varying the discriminability of S2 (intact vs. degraded). Conceptual anticipation was manipulated by varying the amount of information processing required at S2 (easy vs. difficult arithmetic). Motor preparation was varied by requiring a speeded versus a delayed response. No negativity was found before the task stimulus (S2), whereas the probe stimulus (S3) was always preceded by a negative shift. The amplitude of this negative shift was larger under the speed than under the delayed instruction. Its amplitude showed a left-hemisphere preponderance and was larger for the difficult than for the easy condition. ERPs preceding task stimuli seem to reflect functionally different processes from ERPs preceding probe and feedback stimuli. The difference is explained in terms of motivational factors that come into play with feedback and probably play a role in the anticipation of the probe stimulus.     

Subjective and physiological reactivity to chocolate images in high and low chocolate cravers

Cue-reactivity to chocolate images was assessed using self-report and physiological measures. From a pre-screening sample of 454, young women were selected and assigned to high and low chocolate craving groups (N = 36/group). The experimental procedure consisted in the elicitation and measurement of the cardiac defense and startle reflexes while viewing chocolate and standard affective images selected from the International Affective Picture System. In response to chocolate images, high cravers reported more pleasure and arousal but less control than low cravers. In high cravers, viewing chocolate images inhibited the cardiac defense but potentiated the startle reflex, as compared to low cravers. The results confirmed at the physiological level that the motivational state that underlies the experience of chocolate craving include both appetitive (inhibition of the defense reflex) and aversive (potentiation of the startle response) components. The findings supported a motivational conflict theory of chocolate craving.     

Central amygdala ERK signaling pathway is critical to incubation of cocaine craving

Using a rat model of craving and relapse, we have previously found time-dependent increases in cue-induced cocaine seeking over the first months of withdrawal from cocaine, suggesting that drug craving incubates over time. Here, we explored the role of the amygdala extracellular signal-regulated kinase (ERK) signaling pathway in this incubation. Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 withdrawal days than after 1 withdrawal day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 d, but not 1 d, of withdrawal. After 30 d of withdrawal from cocaine, inhibition of central, but not basolateral, amygdala ERK phosphorylation decreased cocaine seeking. After 1 d of withdrawal, stimulation of central amygdala ERK phosphorylation increased cocaine seeking. Results suggest that the incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues.     

Reduced sensory anticipation in migraine

We examined differences between migraine patients and matched healthy controls in anticipatory processes preceding a warning stimulus and preceding a response stimulus during a forewarned choice reaction time task. We manipulated stimulus preceding negativity (SPN) by inserting full response information either at the instant of the warning stimulus (cue) or at the instant of the response stimulus. In contrast to control subjects, migraineurs with aura show low anticipation towards an informative cue and high anticipation towards a noninformative cue. Migraineurs without aura showed a cortical hypoactivation during motor preparation prior to the response stimulus. We propose a functional deficiency within frontal structures or the anterior cingulate cortex in migraine. This might explain the reduced anticipation, as well as the slow responses during selective attention that we previously reported in these patients.     

Does reducing withdrawal severity mediate nicotine patch efficacy? A randomized clinical trial

Nicotine replacement therapy (NRT) repeatedly has been shown to improve smoking treatment outcome. The major mechanism posited for this improvement in outcome is that NRT reduces nicotine craving and withdrawal. The authors tested this hypothesized mechanism of action using real-time data on craving and withdrawal, collected by ecological momentary assessments administered on a palm-top computer. Smokers (N = 324) were randomized to receive either active high-dose (35 mg) 24-hr patches or placebo. Increases in positive affect and decreases in craving, negative affect, and attention disturbance severity were related to lower risk of lapsing. Although NRT treatment did significantly decrease withdrawal and craving severity, these reductions only partially accounted for NRT's impact on time to first lapse: The results from a mediation analysis showed that the hazard ratio for NRT, when controlling for withdrawal and craving severity, was only a third to a half lower than the uncontrolled hazard ratio for NRT alone. This suggests that other mechanisms for the effectiveness of NRT need to be examined.     

The thalamic connections of motor, premotor, and prefrontal areas of cortex in a prosimian primate (Otolemur garnetti)

Connections of motor areas in the frontal cortex of prosimian galagos (Otolemur garnetti) were determined by injecting tracers into sites identified by microstimulation in the primary motor area (M1), dorsal premotor area (PMD), ventral premotor area (PMV), supplementary motor area (SMA), frontal eye field (FEF), and granular frontal cortex. Retrogradely labeled neurons for each injection were related to architectonically defined thalamic nuclei. Nissl, acetylcholinesterase, cytochrome oxidase, myelin, parvalbumin, calbindin, and Cat 301 preparations allowed the ventral anterior and ventral lateral thalamic regions, parvocellular and magnocellular subdivisions of ventral anterior nucleus, and anterior and posterior subdivisions of ventral lateral nucleus of monkeys to be identified. The results indicate that each cortical area receives inputs from several thalamic nuclei, but the proportions differ. M1 receives major inputs from the posterior subdivision of ventral lateral nucleus while premotor areas receive major inputs from anterior parts of ventral lateral nucleus (the anterior subdivision of ventral lateral nucleus and the anterior portion of posterior subdivision of ventral lateral nucleus). PMD and SMA have connections with more dorsal parts of the ventral lateral nucleus than PMV. The results suggest that galagos share many subdivisions of the motor thalamus and thalamocortical connection patterns with simian primates, while having less clearly differentiated subdivisions of the motor thalamus.     

Region-specific distribution of β-amyloid peptide and cytokine expression in TgCRND8 mice

It has recently become clear that alcohol addiction might be related to a brain dysfunction, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse has been linked to abnormal activity in the orbitofrontal cortex, dorsal anterior cingulated cortex (dACC) and amygdala. We report the results of a patient who underwent rTMS targeting the dACC using a double cone coil in an attempt to suppress very severe intractable alcohol craving. Functional imaging studies consisting of fMRI and resting state EEG were performed before rTMS, after successful rTMS and after unsuccessful rTMS with relapse. Craving was associated with EEG beta activity and connectivity between the dACC and PCC in the patient in comparison to a healthy population, which disappeared after successful rTMS. Cue induced worsening of craving pre-rTMS activated the ACC-vmPFC and PCC on fMRI, as well as the nucleus accumbens area, and lateral frontoparietal areas. The nucleus accumbens, ACC-vmPFC and PCC activation disappeared on fMRI following successful rTMS. Relapse was associated with recurrence of ACC and PCC EEG activity, but in gamma band, in comparison to a healthy population. On fMRI nucleus accumbens, ACC and PCC activation returned to the initial activation pattern. A pathophysiological approach is described to suppress alcohol craving temporarily by rTMS directed at the anterior cingulate. Linking functional imaging changes to craving intensity suggests this approach warrants further exploration.