Macaque Orbitofrontal Cortex Research Articles

Heightened Defensive Responses Following Subtotal Lesions of Macaque Orbitofrontal Cortex.

Anxiety disorders are characterized by excessive attention to threat. Several brain areas, including the orbitofrontal cortex (OFC), have been associated with threat processing, with more recent work implicating specialized roles for the medial and lateral subregions of the OFC in mediating specific symptoms of anxiety disorders. Virtually no causal work, however, has evaluated the role of these OFC subregions in regulating behavioral responses under threat. To address this gap, we compared male rhesus monkeys (Macaca mulatta) with bilateral excitotoxic lesions restricted to either the lateral OFC (lOFC), targeting Walker's areas 11 and 13, or the medial OFC (mOFC), targeting Walker's area 14, to a group of unoperated controls on behavioral responses to the presentation of a fake rubber snake, fake spider, and neutral stimuli. Both lesion groups showed heightened defensive and reduced approach responses, accompanied by longer latencies to retrieve a food reward, in the presence of the threatening stimuli. Compared to unoperated controls, the mOFC lesion group also showed longer latencies to reach for rewards and a greater proportion of defensive responses (e.g., piloerection) in the presence of neutral stimuli. Thus, monkeys with mOFC lesions displayed a greater tendency to express defensive responses even in the absence of threat. Overall, our data reveal that both the mOFC and lOFC contribute to the attenuation of defensive responses. Notably, these findings, obtained following selective, excitotoxic lesions of the OFC, are diametrically opposed to the effects of aspiration lesions of OFC observed in macaques.SIGNIFICANCE STATEMENT Engaging in adaptive defensive responses under threat promotes biological fitness. The orbitofrontal cortex (OFC) has been implicated in regulating defensive responses to threat, with distinct subregions likely playing different roles. Here we tested the effects of excitotoxic damage restricted to either the lateral or medial subdivisions of the OFC in rhesus macaques. We found significantly heightened defense and reduced approach responses to threatening stimuli in both lesion groups. While lateral OFC lesions led to an increase in defense responses to the threatening stimuli, medial OFC lesions produced increases in defense responses to both threatening and neutral stimuli. Our findings provide insights into the neural regulation of defensive responses to threat and inform the etiology and treatment of anxiety disorders in humans.

Partial Adaptation to the Value Range in the Macaque Orbitofrontal Cortex.

Values available for choice in different behavioral contexts can vary immensely. To compensate for this variability, neuronal circuits underlying economic decisions undergo adaptation. In orbitofrontal cortex (OFC), neurons encode the subjective value of offered and chosen goods in a quasilinear way. Previous experiments found that the gain of the encoding is lower when the value range is wider. However, the parameters OFC neurons adapted to remained unclear. Furthermore, previous studies did not examine additive changes in neuronal responses. Computational considerations indicate that these factors can directly impact choice behavior. Here we investigated how OFC neurons adapt to changes in the value range. We recorded from two male rhesus monkeys during a juice choice task. Each session was divided into two blocks of trials. In each block, juices were offered within a set range of values, and ranges changed between blocks. Across blocks, neuronal responses adapted to both the maximum and the minimum value, but only partially. As a result, the minimum neural activity was elevated in some value ranges relative to others. Through simulation of a linear decision model, we showed that increasing the minimum response increases choice variability, lowering the expected payoff. This effect is modulated by the balance between cells with positive and negative encoding. The presence of these two populations induces a non-monotonic relationship between the value range and choice efficacy, such that the expected payoff is highest for decisions in an intermediate value range.SIGNIFICANCE STATEMENT Economic decisions are thought to rely on the orbitofrontal cortex (OFC). The values available for choice vary enormously in different contexts. Previous work showed that neurons in OFC encode values in a linear way, and that the gain of encoding is inversely related to the range of available values. However, the specific parameters driving adaptation remained unclear. Here we show that OFC neurons adapt to both the maximum and minimum value in the current context. However, adaptation is partial, leading to contextual changes in the response offset. Interestingly, increasing the activity offset negatively affects choices in a simulated network. Partial adaptation may allow the circuit to maintain information about context value at the cost of slightly reduced payoff.

Reactivation of associative structure specific outcome responses during prospective evaluation in reward-based choices

Before making a reward-based choice, we must evaluate each option. Some theories propose that prospective evaluation involves a reactivation of the neural response to the outcome. Others propose that it calls upon a response pattern that is specific to each underlying associative structure. We hypothesize that these views are reconcilable: during prospective evaluation, offers reactivate neural responses to outcomes that are unique to each associative structure; when the outcome occurs, this pattern is activated, simultaneously, with a general response to the reward. We recorded single-units from macaque orbitofrontal cortex (Area 13) in a riskless choice task with interleaved described and experienced offer trials. Here we report that neural activations to offers and their outcomes overlap, as do neural activations to the outcomes on the two trial types. Neural activations to experienced and described offers are unrelated even though they predict the same outcomes. Our reactivation theory parsimoniously explains these results.

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques.

Cognitive impairments, uncontrolled drinking, and neuropathological cortical changes characterize alcohol use disorder. Dysfunction of the orbitofrontal cortex (OFC), a critical cortical subregion that controls learning, decision-making, and prediction of reward outcomes, contributes to executive cognitive function deficits in alcoholic individuals. Electrophysiological and quantitative synaptomics techniques were used to test the hypothesis that heavy drinking produces neuroadaptations in the macaque OFC. Integrative bioinformatics and reverse genetic approaches were used to identify and validate synaptic proteins with novel links to heavy drinking in BXD mice. In drinking monkeys, evoked firing of OFC pyramidal neurons was reduced, whereas the amplitude and frequency of postsynaptic currents were enhanced compared with controls. Bath application of alcohol reduced evoked firing in neurons from control monkeys, but not drinking monkeys. Profiling of the OFC synaptome identified alcohol-sensitive proteins that control glutamate release (e.g., SV2A, synaptogyrin-1) and postsynaptic signaling (e.g., GluA1, PRRT2) with no changes in synaptic GABAergic proteins. Western blot analysis confirmed the increase in GluA1 expression in drinking monkeys. An exploratory analysis of the OFC synaptome found cross-species genetic links to alcohol intake in discrete proteins (e.g., C2CD2L, DIRAS2) that discriminated between low- and heavy-drinking monkeys. Validation studies revealed that BXD mouse strains with the D allele at the C2cd2l interval drank less alcohol than B allele strains. Thus, by profiling of the OFC synaptome, we identified changes in proteins controlling glutamate release and postsynaptic signaling and discovered several proteins related to heavy drinking that have potential as novel targets for treating alcohol use disorder.SIGNIFICANCE STATEMENT Clinical research identified cognitive deficits in alcoholic individuals as a risk factor for relapse, and alcoholic individuals display deficits on cognitive tasks that are dependent upon the orbitofrontal cortex (OFC). To identify neurobiological mechanisms that underpin OFC dysfunction, this study used electrophysiology and integrative synaptomics in a translational nonhuman primate model of heavy alcohol consumption. We found adaptations in synaptic proteins that control glutamatergic signaling in chronically drinking monkeys. Our functional genomic exploratory analyses identified proteins with genetic links to alcohol and cocaine intake across mice, monkeys, and humans. Future work is necessary to determine whether targeting these novel targets reduces excessive and harmful levels of alcohol drinking.

How Do We Decide? Macaque Orbitofrontal Cortex Neurons Encode Available Options Independently in Subjective Decisions.

How Do We Decide? Macaque Orbitofrontal Cortex Neurons Encode Available Options Independently in Subjective Decisions.

Amygdala Contributions to Stimulus–Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning

Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC.SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus-reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards.

Specialized areas for value updating and goal selection in the primate orbitofrontal cortex.

The macaque orbitofrontal cortex (OFC) is essential for selecting goals based on current, updated values of expected reward outcomes. As monkeys consume a given type of reward to satiety, its value diminishes, and OFC damage impairs the ability to shift goal choices away from devalued outcomes. To examine the contributions of OFC's components to goal selection, we reversibly inactivated either its anterior (area 11) or posterior (area 13) parts. We found that neurons in area 13 must be active during the selective satiation procedure to enable the updating of outcome valuations. After this updating has occurred, however, area 13 is not needed to select goals based on this knowledge. In contrast, neurons in area 11 do not need to be active during the value-updating process. Instead, inactivation of this area during choices causes an impairment. These findings demonstrate selective and complementary specializations within the OFC.

Neurons in the macaque orbitofrontal cortex code relative preference of both rewarding and aversive outcomes

Many studies have shown that the orbitofrontal cortex (OFC) is involved in the processing of emotional information. However, although some lines of study showed that the OFC is also involved in negative emotions, few electrophysiological studies have focused on the characteristics of OFC neuronal responses to aversive information at the individual neuron level. On the other hand, a previous study has shown that many OFC neurons code relative preference of available rewards. In this study, we aimed to elucidate how reward information and aversive information are coded in the OFC at the individual neuron level. To achieve this aim, we introduced the electrical stimulus (ES) as an aversive stimulus, and compared the neuronal responses to the ES-predicting stimulus with those to reward-predicting stimuli. We found that many OFC neurons showed responses to both the ES-predicting stimulus and the reward-predicting stimulus, and they code relative preference of not only the reward outcome but also the aversive outcome. This result suggests that the same group of OFC neurons code both reward and aversive information in the form of relative preference.

Face-selective and auditory neurons in the primate orbitofrontal cortex

Neurons with responses selective for faces are described in the macaque orbitofrontal cortex. The neurons typically respond 2-13 times more to the best face than to the best non-face stimulus, and have response latencies which are typically in the range of 130-220 ms. Some of these face-selective neurons respond to identity, and others to facial expression. Some of the neurons do not have different responses to different views of a face, which is a useful property of neurons responding to face identity. Other neurons have view-dependent responses, and some respond to moving but not still heads. The neurons with face expression, face movement, or face view-dependent responses would all be useful as part of a system decoding and representing signals important in social interactions. The representation of face identity is also important in social interactions, for it provides some of the information needed in order to make different responses to different individuals. In addition, some orbitofrontal cortex neurons were shown to be tuned to auditory stimuli, including for some neurons, the sound of vocalizations. The findings are relevant to understanding the functions of the primate including human orbitofrontal cortex in normal behaviour, and to understanding the effects of damage to this region in humans.

Correspondence of cue activity to reward activity in the macaque orbitofrontal cortex

It has been reported that neurons in the orbitofrontal cortex (OFC) respond to emotionally significant events such as reward-predicting cues and/or the reward itself. The responses to reward-predicting cues are considered to carry the information of the predicted reward. However, few studies have focused on the relationship of the neuronal activity during a cue period with that during a reward period. We can infer that the cue responses of OFC neurons are correlated to the reward responses if they carry the information of the predicted reward. In this study, we focused on neurons that showed responses during both the cue and reward periods, and compared the response characteristics between these periods. We found 94 of 369 OFC neurons showed significant responses during both the cue and reward periods, and 43 of which preserved their selectivity between these periods. Furthermore, population analysis showed that stronger cue responses corresponded to stronger reward responses, and stronger reward responses corresponded to stronger cue responses. These results suggest that individual neurons in the OFC associate visual information with reward information, and contribute to the prediction of future rewards by forming reward representations.

Taste and Related Systems in Primates Including Humans

The cortical processing of taste and related sensory inputs is being investigated at the neuronal level in macaques to help understand the operation of these cortical areas in humans. The primary taste cortex of macaques in the rostral insula and adjoining frontal operculum contains neurons tuned to different tastes including umami (Scott et al., 1986; Yaxley et al., 1990; Baylis and Rolls, 1991; Rolls et al., 1996b, 1998). Neurons in the macaque primary taste cortex respond to the identity and intensity of taste, in that their responses are not affected when taste reward is decreased to zero by feeding to satiety (Rolls et al., 1988). Other neurons in the primary taste cortex respond to somatosensory inputs by representing the viscosity of what is in the mouth, oral fat texture, the temperature of what is in the mouth, capsaicin (Verhagen et al., 2004), and tannic acid (astringency) (Critchley and Rolls, 1996a). Not only are these qualities represented independently by different neurons, but other neurons respond to combinations of these inputs (Verhagen et al., 2004). The macaque primary taste cortex does not represent the smell or sight of food (Verhagen et al., 2004). The macaque orbitofrontal cortex contains the secondary taste and olfactory cortices, in that different parts of it receive from the primary taste cortex (Baylis et al., 1995), and the primary olfactory cortical areas. Neurons in the secondary taste cortex not only represent taste, but other neurons respond to somatosensory inputs by representing the viscosity of what is in the mouth (Rolls et al., 2003b), oral fat texture (Rolls et al., 1999; Verhagen et al., 2003), the temperature of what is in the mouth (Kadohisa et al., 2004), capsaicin (Kadohisa et al., 2004) and tannic acid (astringency) (Critchley and Rolls, 1996a). Other neurons respond to combinations of these inputs. The orbitofrontal cortex also contains neurons that respond to olfactory stimuli and to the sight of food, and for many neurons these olfactory and taste representations are learned by olfactory to taste or visual to taste associative learning (Rolls and Baylis, 1994; Rolls et al., 1996a; Critchley and Rolls, 1996b). Orbitofrontal cortex neurons represent the reward value of what is in the mouth, in that the neuronal responses to the taste, smell, and sight of food decrease to zero as the monkey is fed to satiety (Rolls et al., 1989; Critchley and Rolls, 1996c). Further, orbitofrontal cortex neurons represent sensory-specific reductions in their responses to the particular foods that have been eaten to satiety, and thus implement sensory-specific satiety (Rolls et al., 1999; Critchley and Rolls, 1996c; Rolls, 1999, 2004). In human functional neuroimaging studies, it has been shown that activation of the orbitofrontal cortex (OFC) and adjoining anterior cingulate cortex (ACC) by odours (O’Doherty et al., 2000) and by liquid food (Kringelbach et al., 2003) is hunger-dependent, and indeed the pleasantness of the food is correlated with the degree of activation found. In both studies, it was shown that the modulation is sensory-specific, so that sensory-specific satiety is implemented in the human OFC. The viscosity of food is represented in the human taste and non-taste insula, and in the orbitofrontal cortex (De Araujo and Rolls, 2004). Fat in the mouth is detected by its texture, and this is represented in the anterior cingulate and orbitofrontal cortex (De Araujo and Rolls, 2004). The pleasantness of odours is represented in the orbitofrontal cortex (Rolls et al., 2003a), and flavour representations are formed by combining taste and olfactory inputs in the orbitofrontal cortex (De Araujo et al., 2003b). This primate neurophysiological and human functional neuroimaging evidence thus shows that the orbitofrontal cortex is involved in decoding some primary reinforcers such as taste, odour, texture, touch and temperature; in learning and reversing associations of visual and other stimuli to these primary reinforcers; and in representing the pleasantness of food in a way that correlates directly with whether food is eaten. The orbitofrontal cortex and connected areas play key roles in representing the sensory qualities and affective value of food, and thus in the control of eating (Rolls et al., 1990; Rolls, 1997, 1999, 2000, 2001a,b, 2005; O’Doherty et al., 2001; Rolls and Scott, 2003; Kringelbach and Rolls, 2004).

Orbitofrontal cortex: neuronal representation of oral temperature and capsaicin in addition to taste and texture

The primate orbitofrontal cortex is a site of convergence of information from primary taste, olfactory and somatosensory cortical areas. We describe the discovery of a population of single neurons in the macaque orbitofrontal cortex that responds to the temperature of a liquid in the mouth. The temperature stimuli consisted of water at 10 °C, 23 °C, 37 °C and 42 °C. Twenty-six of the 1149 neurons analyzed (2.3%) responded to oral temperature. The tuning profiles of the neurons to temperature showed that some of the neurons had graded responses to increasing temperature (27%), others responded to cold (10 °C) stimuli (27%), and others were tuned to temperature (46%). The neuronal responses were also measured to taste stimuli, viscosity stimuli (carboxymethyl-cellulose in the range 1–10,000 cP), and capsaicin (10 μM). Of 70 neurons with responses to any of these stimuli, 7.1% were unimodal temperature; 11.3% were temperature and taste-sensitive; 7.1% were temperature and viscosity-sensitive; and 11.3% were temperature, taste and viscosity sensitive. Capsaicin activated 15.7% of the population of responsive neurons tested. These results provide the first evidence of how the temperature of what is in the mouth is represented at the neuronal level in the orbitofrontal cortex and the first evidence for any primate cortical area that in some cases this information converges onto single neurons with inputs produced by other sensory properties of food, including taste and texture. The results provide a basis for understanding how particular combinations of oral temperature, taste, and texture can influence the palatability of foods.

Representations of the texture of food in the primate orbitofrontal cortex: neurons responding to viscosity, grittiness, and capsaicin.

The primate orbitofrontal cortex (OFC) is a site of convergence from taste, olfactory, and somatosensory cortical areas. We describe a population of single neurons in the macaque OFC that responds to the texture of food in the mouth. Use of oral viscosity stimuli consisting of carboxymethylcellulose (CMC) in the range 1-10,000 centipoise showed that the responses of one subset of these neurons were related to stimulus viscosity. Some of the neurons had increasing responses to increasing viscosity, some had decreasing responses, and some neurons were tuned to a range of viscosities. These neurons are a different population to oral fat-sensitive neurons, in that their responses to fats (e.g., safflower oil), to silicone oil [(Si(CH3)2O)n], and to mineral oil (hydrocarbon) depended on the viscosity of these oils. Thus there is a dissociation between texture channels used to sense viscosity and fat. Some of these viscosity-sensitive single neurons were unimodal (somatosensory; 25%) and some received convergent taste inputs (75%). A second subpopulation of neurons responded to gritty texture (produced by microspheres suspended in CMC). A third subpopulation of neurons responded to capsaicin. These results provide evidence about the information channels used to represent the texture and flavor of food in a part of the brain important in appetitive responses to food and are relevant to understanding the physiological and pathophysiological processes related to food intake, food selection, and the effects of variety of food texture in combination with taste and other inputs that affect food intake.