Uncoupling of behavioral and autonomic responses after lesions of the primate orbitofrontal cortex.
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ABSTRACT:
SUBMITTER: Reekie YL
PROVIDER: S-EPMC2447863 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Primate evolution produced an increased capacity to respond flexibly to varying social contexts as well as expansion of the prefrontal cortex. Despite this association, how prefrontal neurons respond to social information remains virtually unknown. People with damage to their orbitofrontal cortex (OFC) struggle to recognize facial expressions, make poor social judgments, and frequently make social faux pas. Here we test explicitly whether neurons in primate OFC signal social information and, if so, how such signals compare with responses to primary fluid rewards. We find that OFC neurons distinguish images that belong to socially defined categories, such as female perinea and faces, as well as the social dominance of those faces. These modulations signaled both how much monkeys valued these pictures and their interest in continuing to view them. Far more neurons signaled social category than signaled fluid value, despite the stronger impact of fluid reward on monkeys' choices. These findings indicate that OFC represents both the motivational value and attentional priority of other individuals, thus contributing to both the acquisition of information about others and subsequent social decisions. Our results betray a fundamental disconnect between preferences expressed through overt choice, which were primarily driven by the desire for more fluid, and preferential neuronal processing, which favored social computations.
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Project description:In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.
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Project description:The primate amygdala sends dense projections to posterior orbitofrontal cortex (pOFC) in pathways that are critical for processing emotional content, but the synaptic mechanisms are not understood. We addressed this issue by investigating pathways in rhesus monkeys (Macaca mulatta) from the amygdala to pOFC at the level of the system and synapse. Terminations from the amygdala were denser and larger in pOFC compared with the anterior cingulate cortex, which is also strongly connected with the amygdala. Axons from the amygdala terminated most densely in the upper layers of pOFC through large terminals. Most of these terminals innervated spines of presumed excitatory neurons and many were frequently multisynaptic and perforated, suggesting high synaptic efficacy. These amygdalar synapses in pOFC exceeded in size and specialization even thalamocortical terminals from the prefrontal-related thalamic mediodorsal nucleus to the middle cortical layers, which are thought to be highly efficient drivers of cortical neurons. Pathway terminals in the upper layers impinge on the apical dendrites of neurons in other layers, suggesting that the robust amygdalar projections may also activate neurons in layer 5 that project back to the amygdala and beyond to autonomic structures. Among inhibitory neurons, the amygdalar pathway innervated preferentially the neurochemical classes of calbindin and calretinin neurons in the upper layers of pOFC, which are synaptically suited to suppress noise and enhance signals. These features provide a circuit mechanism for flexibly shifting focus and adjusting emotional drive in processes disrupted in psychiatric disorders, such as phobias and obsessive-compulsive disorder.
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Project description:Primates depend for their survival on their ability to understand their social environment, and their behavior is often shaped by social circumstances. We report that the orbitofrontal cortex, a brain region involved in motivation and reward, is tuned to social information. Macaque monkeys worked to collect rewards for themselves and two monkey partners. Behaviorally, monkeys discriminated between cues signaling large and small [corrected] rewards, and between cues signaling rewards to self only and reward to both self and another monkey, with a preference for the former over the latter in both instances. Single neurons recorded during this task encoded the meaning of visual cues that predicted the magnitude of future rewards, as well as the motivational value of rewards obtained in a social context. Furthermore, neuronal activity was found to track momentary social preferences and partner's identity and social rank. The orbitofrontal cortex thus contains key neuronal mechanisms for the evaluation of social information.
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Project description:The subgenual anterior cingulate cortex (subgenual ACC) plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions. Using Pavlovian conditioning procedures in macaque monkeys, we examined the contribution of the subgenual ACC to autonomic arousal associated with positive emotional events. After such conditioning, autonomic arousal increases in response to cues that predict rewards, and monkeys maintain this heightened state of arousal during an interval before reward delivery. Here we show that although monkeys with lesions of the subgenual ACC show the initial, cue-evoked arousal, they fail to sustain a high level of arousal until the anticipated reward is delivered. Control procedures showed that this impairment did not result from differences in autonomic responses to reward delivery alone, an inability to learn the association between cues and rewards, or to alterations in the light reflex. Our data indicate that the subgenual ACC may contribute to positive affect by sustaining arousal in anticipation of positive emotional events. A failure to maintain positive affect for expected pleasurable events could provide insight into the pathophysiology of psychological disorders in which negative emotions dominate a patient's affective experience.
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Project description:Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. 18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced reward blunting, illustrating the symptom-specificity of its actions.
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Project description:Contemporary models of behavioral regulation maintain that balanced activity between cognitive control areas (prefrontal cortex, PFC) and subcortical reward-related regions (nucleus accumbens, NAC) mediates the selection of appropriate behavioral responses, whereas imbalanced activity (PFC < NAC) results in maladaptive behavior [1-6]. Imbalance can arise from reduced engagement of PFC (via fatigue or stress [7]) or from excessive activity in NAC [8]. Additionally, a concept far less researched is that an imbalance can result from simultaneously low PFC activity and high NAC activity. This occurs during adolescence, when the maturation of PFC lags behind that of NAC and NAC is more functionally active compared to adulthood or pre-adolescence [2, 5, 9, 10]. Accordingly, activity is disproportionately higher in NAC than in PFC, which may contribute to impulsivity and risk-taking exhibited by adolescents [5, 6, 10-12]. Despite having explanatory value, support for this notion has been solely correlational. Here, we causally tested this using chemogenetics to simultaneously decrease neural activity in the orbitofrontal cortex (OFC) and increase activity in NAC in adult rats, mimicking the imbalance during adolescence. We tested the effects on negative occasion setting, an important yet understudied form of inhibitory learning that may be particularly relevant during adolescence. Rats with combined manipulation of OFC and NAC were impaired in learning to use environmental cues to withhold a response, an effect that was greater than that of either manipulation alone. These findings provide direct evidence that simultaneous underactivity in OFC and overactivity in NAC can negatively impact behavioral control and provide insight into the neural systems that underlie inhibitory learning.
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Project description:Attentional bias to drug-associated cues correlates with extent of current use, and risk of relapse among those attempting abstinence. Electroencephalogram (EEG) and functional imaging measures in clinical studies have previously investigated the neural basis of attentional bias, but the lack of animal models precluded investigation at the single-unit level. To complement results obtained from clinical studies, we have employed a non-human primate model of attentional bias to cocaine cues while simultaneously recording single-unit activity in cortical and striatal regions implicated in reward processing. Rhesus macaques conditioned to associate particular colors with cocaine or water reward performed an attentional bias task, in which those colors served as irrelevant distractors. Concurrently, multiple electrode arrays for recording single-unit activity were acutely implanted into the orbitofrontal cortex, anterior cingulate cortex, dorsal anterior striatum, and ventral striatum. As in clinical studies, attentional bias was indicated by elongated response times on trials with cocaine-associated distractors compared with trials with water-associated, or control unconditioned distractors. In both animals studied, across an unbiased sample of neurons, the orbitofrontal cortex differentiated distractor condition by the proportion of single-units activated, as well as by population response. In one of the two, the anterior cingulate cortex did as well, but neither striatal region did in either animal. These direct measures of single-unit activity in a primate model complement clinical imaging observations suggesting that cortical mechanisms, especially in orbitofrontal cortex, are likely involved in attentional bias to cocaine-associated environmental cues.
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Project description:To successfully evaluate potential courses of action and choose the most favorable, we must consider the outcomes that may result. Many choices involve risk, our assessment of which may lead us to success or failure in matters financial, legal or health-related. The orbitofrontal cortex (OFC) has been implicated as critical for evaluating choices based on risk. To measure how outcomes of risky decisions are represented in the OFC, we recorded the electrophysiological activity of single neurons while rats made behavioral responses to obtain rewards under conditions of either certainty or risk. Rats exhibited different risk-preferences when given the opportunity to choose. In risk-preferring rats, OFC responses were enhanced following the delivery of large rewards obtained under risk compared with smaller, certain rewards and reward omission. However, in risk-neutral rats, neurons showed similarly enhanced responses to both large rewards obtained under risk and smaller, certain rewards compared with reward omission. Thus, the responses of OFC neurons reflected the subjective evaluation of outcomes in individuals with different risk-preferences. Such enhanced neural responding to risky rewards may serve to bias individuals towards risk-preference in decision-making.
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Project description:Determining insular functional topography is essential for assessing autonomic consequences of neural injury. We examined that topography in the five major insular cortex gyri to three autonomic challenges, the Valsalva, hand grip, and foot cold pressor, using functional magnetic resonance imaging (fMRI) procedures. Fifty-seven healthy subjects (age ± std: 47 ± 9 years) performed four 18 s Valsalva maneuvers (30 mm Hg load pressure), four hand grip challenges (16 s at 80% effort), and a foot cold pressor (60 s, 4°C), with fMRI scans recorded every 2 s. Signal trends were compared across gyri using repeated measures ANOVA. Significantly (P<0.05) higher signals in left anterior versus posterior gyri appeared during Valsalva strain, and in the first 4 s of recovery. The right anterior gyri showed sustained higher signals up to 2 s post-challenge, relative to posterior gyri, with sub-gyral differentiation. Left anterior gyri signals were higher than posterior areas during the hand grip challenge. All right anterior gyri showed increased signals over posterior up to 12 s post-challenge, with decline in the most-anterior gyrus from 10 to 24 s during recovery. The left three anterior gyri showed relatively lower signals only during the 90 s recovery of the cold pressor, while the two most-anterior right gyri signals increased only during the stimulus. More-differentiated representation of autonomic signals appear in the anterior right insula for the Valsalva maneuver, a bilateral, more-posterior signal representation for hand grip, and preferentially right-sided, anterior-posterior representation for the cold pressor. The functional organization of the insular cortex is gyri-specific to unique autonomic challenges.
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