Addiction: beyond dopamine reward circuitry

Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.     

Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place

Predicting reward is essential in learning approach behaviors. Dopaminergic activity has been implicated in reward, movement, and cognitive processes, all essential elements in learning. The nucleus accumbens (NAc) receives converging inputs from corticolimbic information-processing areas and from mesolimbic dopamine neurons originating in the ventral tegmental area. Previously, we reported that in mice, a dopamine D2 receptor knockout (D2R-KO) eliminated the prereward inhibitory response, increased place-field size of NAc neurons, and reduced locomotor activity without marked change in intracranial self-stimulation (ICSS) behavior. The present study investigated the specific contribution of dopamine D1 receptor (D1R) in mediating reward, locomotor activity, and spatial associative processes and in regulating NAc neural responses. In contrast to D2R-KO animals, here we find D1R-KO in mice selectively eliminated the prereward excitatory response and decreased place-field size of NAc neurons. Furthermore, D1R-KO impaired ICSS behavior, seriously reduced locomotor activity, and retarded acquisition of a place learning task. Thus, the present results suggest that D1R may be an important determinant in brain stimulation reward (ICSS) and participates in coding for a type of reward prediction of NAc neurons and in spatial learning.     

Learning reward timing in cortex through reward dependent expression of synaptic plasticity

The ability to represent time is an essential component of cognition but its neural basis is unknown. Although extensively studied both behaviorally and electrophysiologically, a general theoretical framework describing the elementary neural mechanisms used by the brain to learn temporal representations is lacking. It is commonly believed that the underlying cellular mechanisms reside in high order cortical regions but recent studies show sustained neural activity in primary sensory cortices that can represent the timing of expected reward. Here, we show that local cortical networks can learn temporal representations through a simple framework predicated on reward dependent expression of synaptic plasticity. We assert that temporal representations are stored in the lateral synaptic connections between neurons and demonstrate that reward-modulated plasticity is sufficient to learn these representations. We implement our model numerically to explain reward-time learning in the primary visual cortex (V1), demonstrate experimental support, and suggest additional experimentally verifiable predictions.     

Physiological state gates acquisition and expression of mesolimbic reward prediction signals

Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors.Reconciling differences between anticipated and experienced outcomes is fundamental for how an organism learns about the world. A key component of temporal difference (TD) learning models is the reward prediction error (RPE) term (1, 2), which is thought to be represented by phasic activity of midbrain dopamine neurons (3–5). Indeed, conditioned stimulus (CS)-related dopamine activity correlates with multiple behavioral indices of learning (6–8), and phasic dopamine signaling is sufficient to drive CS-unconditioned stimulus (US) learning (9).In much of the supportive empirical work, food- or fluid-restricted animals first experience and then learn to anticipate an innately appetitive US (e.g., sucrose, juice, water). Thus, the US always has an inherent caloric, nutritive, or positive affective value to the organism. Consequently, it is uncertain whether dopamine neurons can acquire CS-US associations without first experiencing the US as a reward. Resolving this question is critical, because the striatal underpinnings of goal-directed behavior may encompass both RPE and experience-independent, model-based strategies (10, 11). One way to delineate dopamine’s role in these different learning strategies would be to promote associations between a CS and a neutral or normally avoided US whose affective value could be manipulated and then determine the experience dependency of dopamine CS responses.Sodium appetite is an ideal platform on which to address this question. Sodium depletion induces a powerful sodium hunger and radically but reversibly alters the rewarding value of hypertonic NaCl solutions (12, 13). The appetite is highly selective for sodium and manifests independent of prior experience with either sodium solutions or sodium deficiency (14, 15). Therefore, sodium appetite facilitates the delivery of a US (hypertonic NaCl) that is rewarding only in a specific physiological state. We measured phasic dopamine signaling in the nucleus accumbens (NAc) of rats while delivering a hypertonic NaCl solution directly into the oral cavity (intraoral) while rats were under different physiological states. We found that dopamine responses to the NaCl US were state-dependent and used this feature to investigate how physiological state influenced acquisition and expression of NaCl CS-US associations. In contrast to the US, dopamine responses to the NaCl CS depended on an interaction between experience and physiological state. Our data suggest that dopamine neurons only signal reward predictions after extensive and direct, state-dependent experience with an appetitive US and, moreover, that reward prediction signals are expressed in a state-dependent manner, a finding most consistent with TD models.     

Temporal isolation of neural processes underlying face preference decisions

Decisions about whether we like someone are often made so rapidly from first impressions that it is difficult to examine the engagement of neural structures at specific points in time. Here, we used a temporally extended decision-making paradigm to examine brain activation with functional MRI (fMRI) at sequential stages of the decision-making process. Activity in reward-related brain structures-the nucleus accumbens (NAC) and orbitofrontal cortex (OFC)-was found to occur at temporally dissociable phases while subjects decided which of two unfamiliar faces they preferred. Increases in activation in the OFC occurred late in the trial, consistent with a role for this area in computing the decision of which face to choose. Signal increases in the NAC occurred early in the trial, consistent with a role for this area in initial preference formation. Moreover, early signal increases in the NAC also occurred while subjects performed a control task (judging face roundness) when these data were analyzed on the basis of which of those faces were subsequently chosen as preferred in a later task. The findings support a model in which rapid, automatic engagement of the NAC conveys a preference signal to the OFC, which in turn is used to guide choice.     

Laminar and columnar auditory cortex in avian brain

The mammalian neocortex mediates complex cognitive behaviors, such as sensory perception, decision making, and language. The evolutionary history of the cortex, and the cells and circuitry underlying similar capabilities in nonmammals, are poorly understood, however. Two distinct features of the mammalian neocortex are lamination and radially arrayed columns that form functional modules, characterized by defined neuronal types and unique intrinsic connections. The seeming inability to identify these characteristic features in nonmammalian forebrains with earlier methods has often led to the assumption of uniqueness of neocortical cells and circuits in mammals. Using contemporary methods, we demonstrate the existence of comparable columnar functional modules in laminated auditory telencephalon of an avian species (Gallus gallus). A highly sensitive tracer was placed into individual layers of the telencephalon within the cortical region that is similar to mammalian auditory cortex. Distribution of anterograde and retrograde transportable markers revealed extensive interconnections across layers and between neurons within narrow radial columns perpendicular to the laminae. This columnar organization was further confirmed by visualization of radially oriented axonal collaterals of individual intracellularly filled neurons. Common cell types in birds and mammals that provide the cellular substrate of columnar functional modules were identified. These findings indicate that laminar and columnar properties of the neocortex are not unique to mammals and may have evolved from cells and circuits found in more ancient vertebrates. Specific functional pathways in the brain can be analyzed in regard to their common phylogenetic origins, which introduces a previously underutilized level of analysis to components involved in higher cognitive functions.     

Memory formation and retrieval of neuronal silencing in the auditory cortex

Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior.Cortical neurons exhibit spontaneous activity without explicit external stimuli (1–3), which may not only increase, but also be suppressed, by sensory stimuli (4, 5). For example, auditory stimuli suppress a subset of auditory cortical neurons in a frequency-dependent manner (5). Synaptic inhibition in the cerebral cortex is fundamental for neuronal modulation (6), including gain control (7), response selectivity (8, 9), and synchronized activities (10, 11). Inhibition-based modulations may contribute to stimulus-driven behaviors and associative memories of sensory stimuli (12); however, it remains unclear whether neuronal silencing (i.e., a transient reduction in firing rates from their spontaneous level) by itself can serve as a memory trace and bring about behavioral expressions. In this study, we tested this possibility by optogenetically silencing auditory cortical neurons.     

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

Anxiety commonly co‐occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Anxiety disorders and obsessive-compulsive disorder (OCD) are disabling psychiatric conditions and the major contributors to global burden of nonfatal illness (1). OCD is characterized by recurrent thoughts (obsessions) and/or repetitive behaviors (compulsions) that are aimed at reducing the anxiety caused by obsessions (2, 3), indicating a close correlation between anxiety and OCD. Indeed, anxiety disorders have been reported epidemiologically as the most frequent comorbid conditions with OCD (3, 4). Therefore, common pathologies may be present in anxiety disorders and OCD, and elucidation of the shared neural substrates will lead to greater insight into their pathophysiology and treatment.The nucleus accumbens (NAc) is a main component of the ventral striatum and a pivotal node in limbic basal ganglia loop, whose dysfunction may result in psychiatric diseases such as anxiety and OCD (5, 6). Accumulating experimental and clinical evidence indicates that the NAc, particularly the core compartment, holds a key position in motivation, emotion, and cognition and is strongly implicated in the psychopathology and treatment of anxiety and OCD. It has been reported that trait anxiety and OCD risk are positively correlated with the volume of NAc (7, 8). Functional neuroimaging reveals that the NAc activation correlates positively with the severity of human anxiety and obsessive-compulsive symptoms in OCD patients (9, 10). More importantly, deep brain stimulation (DBS) targeting the NAc core has been found to improve obsessive-compulsive symptoms and decrease ratings of anxiety in patients suffering from treatment-resistant OCD or depression (11, 12). Therefore, NAc core may be a potential common neural substrate for the clinical and neuropathological overlap between anxiety and OCD.The NAc core receives dense glutamatergic projections from the limbic system, including the prefrontal cortex, basolateral amygdala (BLA), and ventral hippocampus (vHipp), and integrates cognitive and affective information to instigate motivational approach behaviors (13, 14). In addition, the NAc core is regulated by various neuromodulators, such as orexin, serotonin, and histamine, from several brain regions (15–17). Among them, central histamine is synthesized and released by the histaminergic neurons restrictedly concentrated in the tuberomammillary nucleus (TMN) of the hypothalamus and serves as a general modulator for whole-brain activity via the mediation of histamine H1 to H4 receptors (18, 19). Accordingly, the aberrant histamine signaling is closely associated with sleep, motor, cognitive, and psychiatric conditions (18, 20, 21). In the clinic, drugs targeting the presynaptic H3 receptor have been used for prescribed treatment of various psychiatric and neurologic disorders (22). Interestingly, a high density of the H3 receptor has been found in NAc (23, 24). Therefore, in the present study, we create a transgenic rat strain expressing Cre recombinase in histidine decarboxylase (HDC, the histamine-synthesizing enzyme) neurons and employ anterograde axonal tract tracings, whole-cell patch clamp recordings, optogenetic and chemogenetic manipulation, and behavioral tests to explore the role of hypothalamic histaminergic afferents and the H3 receptor in the NAc core in regulation of anxiety and obsessive-compulsive-like behaviors. We find that optogenetic activation of hypothalamic TMN–NAc core histaminergic projections produces an anxiolytic effect and ameliorates obsessive-compulsive-like behaviors induced by restraint stress, which is due to H3 receptor–mediated suppression of glutamatergic transmission in a common prelimbic prefrontal cortex (PrL)–NAc core pathway.     

Alterations of functional connectivity in auditory and sensorimotor neural networks: A case report in a patient with cortical deafness after bilateral putaminal hemorrhagic stroke

Rationale:Cortical deafness is a rare auditory dysfunction caused by damage to brain auditory networks. The aim was to report alterations of functional connectivity in intrinsic auditory, motor, and sensory networks in a cortical deafness patient.Patient concerns:A 41-year-old woman suffered a right putaminal hemorrhage. Eight years earlier, she had suffered a left putaminal hemorrhage and had minimal sequelae. She had quadriparesis, imbalance, hypoesthesia, and complete hearing loss.Diagnoses:She was diagnosed with cortical deafness. After 6 months, resting-state functional magnetic resonance imaging (rs-fMRI) and diffuse tensor imaging (DTI) were performed. DTI revealed that the acoustic radiation was disrupted while the corticospinal tract and somatosensory track were intact using deterministic tracking methods. Furthermore, the patient showed decreased functional connectivity between auditory and sensorimotor networks.Interventions:The patient underwent in-patient stroke rehabilitation therapy for 2 months.Outcomes:Gait function and ability for activities of daily living were improved. However, complete hearing impairment persisted in 6 months after bilateral putaminal hemorrhagic stroke.Lessons:Our case report seems to suggest that functional alterations of spontaneous neuronal activity in auditory and sensorimotor networks are related to motor and sensory impairments in a patient with cortical deafness.     

Selective memory retrieval of auditory what and auditory where involves the ventrolateral prefrontal cortex

There is evidence from the visual, verbal, and tactile memory domains that the midventrolateral prefrontal cortex plays a critical role in the top–down modulation of activity within posterior cortical areas for the selective retrieval of specific aspects of a memorized experience, a functional process often referred to as active controlled retrieval. In the present functional neuroimaging study, we explore the neural bases of active retrieval for auditory nonverbal information, about which almost nothing is known. Human participants were scanned with functional magnetic resonance imaging (fMRI) in a task in which they were presented with short melodies from different locations in a simulated virtual acoustic environment within the scanner and were then instructed to retrieve selectively either the particular melody presented or its location. There were significant activity increases specifically within the midventrolateral prefrontal region during the selective retrieval of nonverbal auditory information. During the selective retrieval of information from auditory memory, the right midventrolateral prefrontal region increased its interaction with the auditory temporal region and the inferior parietal lobule in the right hemisphere. These findings provide evidence that the midventrolateral prefrontal cortical region interacts with specific posterior cortical areas in the human cerebral cortex for the selective retrieval of object and location features of an auditory memory experience.Functional neuroimaging studies have established a relationship between the ventrolateral prefrontal cortex and certain aspects of memory retrieval. For instance, there is evidence for the involvement of the left ventrolateral prefrontal region in selective verbal retrieval, such as the free recall of words that appear within particular contexts (lists) (1), verbal fluency (a form of selective verbal retrieval from semantic memory) (2, 3), and various other forms of verbal semantic retrieval (4–6). More precisely, it has been proposed that the two midventrolateral prefrontal cortical areas 45 and 47/12 are critical for the active selection and retrieval of information from memory when stimuli are related to other stimuli/contexts in multiple and more-or-less equiprobable ways, so that memory retrieval cannot be a matter of mere recognition of the stimuli or supported by strong and unique stimulus-to-stimulus or stimulus-to-context associations (7). In previous functional neuroimaging studies, we were able to show activity increases that were specific to the midventrolateral prefrontal cortex for the active retrieval of visual and tactile stimuli (8, 9). A more recent study has shown that patients with lesions to the ventrolateral prefrontal region, but not those with lesions involving the dorsolateral prefrontal region, show impairments in the active controlled retrieval of the visual contexts within which words had appeared (10). This impairment was not accompanied by general memory loss of the type observed after limbic medial temporal lobe lesions (11–13). Patients with ventrolateral prefrontal lesions performed as well as normal control subjects on recognition memory of the presented stimuli, but were impaired when they were asked to retrieve selectively specific aspects of the memorized information in a task in which words and their context entered into multiple relations with each other across trials and, therefore, retrieval could not be supported by simple recognition memory (10). Taken together, these results suggest that the midventrolateral prefrontal cortex plays a critical role in the top–down modulation of activity for the retrieval of specific features of mnemonic information when simple familiarity and/or unambiguous stimulus-to-stimulus relations are not sufficient for memory retrieval.Although there is considerable evidence of direct anatomical connections between auditory cortical regions in the temporal lobe and the ventrolateral prefrontal cortex (14–20) and the presence of auditory responsive neurons for complex sounds in the ventrolateral prefrontal cortex (21, 22), there is no study examining the potential involvement of the ventrolateral prefrontal region in the controlled selective retrieval of auditory nonverbal information in the human brain. Most studies investigating the role of the prefrontal cortex in the auditory domain have focused on verbal phonological and semantic memory (23–25). The aim of the present study was to examine the hypothesis that the midventrolateral prefrontal cortex is involved in the active controlled retrieval of nonverbal auditory information from memory, in a manner analogous to its previously demonstrated role in the retrieval of verbal and nonverbal visual and tactile information (8, 9, 26).In the present functional magnetic resonance imaging (fMRI) study, on each trial, one of four different melodies was presented from one of four locations in a virtual acoustic environment (Fig. 1A) and, after a short delay, the subjects were instructed via a cue to retrieve either the specific melody (regardless of its location) or the location (regardless of the melody that was presented there) (Fig. 1B). The subjects were thus required to isolate the instructed component of the previously memorized auditory stimulus complex, namely the melody or the location. The experimental design prevented the establishment of strong and unique relations between the melodies and the locations because, across trials, all four melodies were presented from each one of the four locations with equal probability. Intermixed with these “active retrieval” trials requiring the isolation of a specific feature of the stimulus complex were “recognition” control trials that were identical in terms of the initial stimulus presentation period but, following the delay, the subjects were instructed simply to recognize (based on familiarity) the previously encoded stimulus complex of the melody and its location. No isolation of a specific aspect of the memory (melody or location) was required in these recognition control trials. There were also “baseline” control trials in which no auditory stimulus was presented during the retrieval period. The hypothesis to be tested predicted selective activity increases in the midventrolateral prefrontal cortex during the active retrieval of specific aspects of the encoded auditory stimuli in comparison with the simple recognition of that stimulus, that is, during the test period of the active retrieval trials versus the same period in the recognition control trials.Open in a separate windowFig. 1.Schematic diagram of the experimental paradigm and scanning protocol. (A) Locations used to present the melodies. Gray indicates the four locations that were used only during the test period of the recognition control trials. (B) Illustration of the testing procedure. All trials started with the presentation of a cross in the middle of the screen followed by the encoding period, during which the auditory stimulus was presented. After a variable delay, a visual instructional cue was presented and the test period followed after the disappearance of the visual cue. A second auditory stimulus was presented during the test period for the experimental and recognition control trials but not during the baseline control trials. The subjects’ responses were recorded during the test period. The duration of the various periods was the same for the experimental and control trials. (C) Illustration of the sparse-sampling fMRI scanning used in this experiment.     

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the μ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the μ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral–ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.     

Hierarchical excitatory synaptic connectivity in mouse olfactory cortex

Topological motifs in synaptic connectivity—such as the cortical column—are fundamental to processing of information in cortical structures. However, the mesoscale topology of cortical networks beyond columns remains largely unknown. In the olfactory cortex, which lacks an obvious columnar structure, sensory-evoked patterns of activity have failed to reveal organizational principles of the network and its structure has been considered to be random. We probed the excitatory network in the mouse olfactory cortex using variance analysis of paired whole-cell recording in olfactory cortex slices. On a given trial, triggered network-wide bursts in disinhibited slices had remarkably similar time courses in widely separated and randomly selected cell pairs of pyramidal neurons despite significant trial-to-trial variability within each neuron. Simulated excitatory network models with random topologies only partially reproduced the experimental burst-variance patterns. Network models with local (columnar) or distributed subnetworks, which have been predicted as the basis of encoding odor objects, were also inconsistent with the experimental data, showing greater variability between cells than across trials. Rather, network models with power-law and especially hierarchical connectivity showed the best fit. Our results suggest that distributed subnetworks are weak or absent in the olfactory cortex, whereas a hierarchical excitatory topology may predominate. A hierarchical excitatory network organization likely underlies burst generation in this epileptogenic region, and may also shape processing of sensory information in the olfactory cortex.Structural and functional plasticity at excitatory synapses in cortical networks represents a fundamental mechanism for encoding sensory representations and memory. As a result, neuronal ensembles that are connected with high probability emerge as functional units to produce a population code of the environment. The topology of such excitatory circuits should contain signatures—as global topological motifs—that reflect the encoding strategy. The cortical column is a well-studied example of such a motif (1). Columnar cortices contain substantial distributed connectivity and some brain areas, such as association cortex, high-order cortices, and the piriform cortex, lack a pronounced columnar structure. In the piriform (olfactory) cortex, there exists only a rudimentary understanding of the relationship between network structure and cortical function. The axons of individual piriform pyramidal neurons ramify widely throughout the olfactory cortex, and only show patchiness on a very broad scale (2–4). Consistent with this architecture, neural activity in response to individual odorants is distributed broadly across the olfactory cortex as detected by 2-deoxyglucose, c-fos expression, multiunit recording, and population calcium imaging (5–8). Likewise, the receptive fields of individual neurons in piriform cortex and anterior olfactory cortex are broad (9, 10). Broad receptive fields in piriform cortex reflect convergence of input from many olfactory bulb glomeruli (11) and are strongly influenced by recurrent connectivity (12).These observations support a highly distributed population representation but reveal little about what processing function the piriform cortex performs. Physiological and anatomical studies have provided some clues. For example, neuronal responses in piriform cortex are specific for category of odorant (13), and odor identity and similarity are separately encoded in anterior and posterior piriform cortex, respectively (14), suggesting hierarchical coding. The endopiriform (EN) and preendopiriform nucleus (pEN), immediately subjacent to the piriform cortex, have dense recurrent connectivity and dense connectivity with overlying areas of piriform cortex (15, 16). The pEN, also called area tempestas, is a highly epileptogenic locus (16, 17). However, the physiological role of its dense connectivity is unknown (15, 18).To probe excitatory connectivity in the olfactory cortex, we isolated excitatory synaptic activity in a tailored brain slice containing the ventral anterior piriform cortex (APC_V), the pEN, the anterior olfactory cortex (AOC; also called anterior olfactory nucleus). Using weak stimulation of the lateral olfactory tract (LOT) input while blocking GABAergic inhibition and NMDA receptors, we evoked transient, all-or-none, network-wide bursts of excitation. Network-wide transient bursts are a dynamic circuit property shared by the hippocampus, neocortex, and piriform cortex in disinhibited recording conditions (19–21). We used the pairwise variance patterns detectable in the fine structure of these bursts as a probe of excitatory network topology. We compared whole-cell recordings from randomly selected pairs of principal neurons in olfactory cortex with patterns generated in simulated networks with a range of network topologies. Our findings suggest that excitatory connectivity in olfactory cortex is neither random nor organized into local or distributed subnetworks. Rather, it shows hierarchical connectivity.     

Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex

Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted “U” relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased, and the relationship between HR and RTs was altered. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a population-coding analysis, we show that after bilateral amygdala lesions, the balance of encoding in dACC is skewed away from signaling either reward value or choice direction toward HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.

Our current bodily state, whether it be thirst or a racing heart, affects ongoing cognitive processes. Bodily arousal is fundamental to representations of our bodily state and can have a marked influence on decision-making (1–3). At moderate levels, bodily arousal can increase the chance of survival by invigorating responding, whereas at higher levels, it promotes defensive behaviors such as freezing when threat of predation is imminent (4, 5). Consequently, altered generation and assessment of bodily arousal is thought to contribute to a host of psychiatric disorders such as anxiety disorders and addiction (6–8).The influence of bodily arousal on behavior can be accounted for by viscerosensory feedback from the body reaching the brain. Central representations of current bodily state including arousal are known as interoception, and these representations are thought to be essential for maintaining homeostasis (9). Several brain areas including the dorsal anterior cingulate cortex (dACC), orbitofrontal cortex (OFC), anterior insular cortex, hypothalamus, and amygdala are implicated in interoception, signaling bodily arousal as well as other aspects of physiological state, such as hydration and temperature (10–13). The network of areas spanning frontal and limbic structures highlighted previously as central to interoception overlaps extensively with the parts of the brain that are essential for reward-guided decision-making, and these shared neural substrates are likely where these two processes interact (14, 15). Notably, lesions or dysfunction within frontal cortex and limbic areas in either humans or monkeys is associated with altered bodily arousal, interoception, and decision-making (16–18). Thus, optimal levels of bodily arousal are essential for appropriate responding to appetitive or aversive stimuli and likely require flexible adjustment of population-level neural representation in frontal and limbic structures (19).Despite the appreciation that limbic and frontal structures are critical to both decision-making and interoception, how these processes interact in the frontal cortex at the level of single neurons is poorly understood. This is because single-neuron investigations of choice behavior have rarely considered or even attempted to measure the influence of bodily arousal on decision-making. Even less certain is how heightened states of bodily arousal affect interoceptive representations at the level of single neurons and subsequently influence choice behavior.To address this, we analyzed a rare dataset: electrocardiogram (ECG) data were recorded simultaneously with single-neuron recordings in OFC and dACC in macaque monkeys performing a reward-guided task both before and after excitotoxic lesions of the amygdala (20). In this previous study, we demonstrated that the decisions of monkeys were guided by the reward size associated with each option. In addition, we found that the reaction times (RTs) to choose rewarded options reflected the expected amount of reward. Correspondingly, the activity of a large proportion of single neurons in OFC and dACC preferentially encoded reward value. Here, our aim was to examine the potential interaction between factors that guide decision-making on a trial-by-trial basis (i.e., reward value and choice direction) and representations of bodily arousal in frontal cortex. For this purpose, we define heart rate (HR) as bodily arousal and its neural representation as interoception. The HR during the fixation period of each trial (baseline HR) was used as a proxy of the current bodily arousal (21). Selective lesions of the amygdala caused a tonic increase in baseline HR, which was seen both during reward-guided behavior (22) and at rest. Here, we report that this increase in HR altered the influence of bodily arousal on decision-making, whereby heightened bodily arousal was associated with slower responding. At the same time, single neuron correlates of baseline HR increased in dACC, but not OFC, after amygdala lesions, altering the balance of coding away from decision-relevant processes and toward representations of bodily arousal. Taken together, this pattern of results suggests that bilateral amygdala lesions caused a state of hyperarousal, which impacts decision-making through adjustments in population coding in dACC.     

Transformation of acoustic information to sensory decision variables in the parietal cortex

The process by which sensory evidence contributes to perceptual choices requires an understanding of its transformation into decision variables. Here, we address this issue by evaluating the neural representation of acoustic information in the auditory cortex-recipient parietal cortex, while gerbils either performed a two-alternative forced-choice auditory discrimination task or while they passively listened to identical acoustic stimuli. During task engagement, stimulus identity decoding performance from simultaneously recorded parietal neurons significantly correlated with psychometric sensitivity. In contrast, decoding performance during passive listening was significantly reduced. Principal component and geometric analyses revealed the emergence of low-dimensional encoding of linearly separable manifolds with respect to stimulus identity and decision, but only during task engagement. These findings confirm that the parietal cortex mediates a transition of acoustic representations into decision-related variables. Finally, using a clustering analysis, we identified three functionally distinct subpopulations of neurons that each encoded task-relevant information during separate temporal segments of a trial. Taken together, our findings demonstrate how parietal cortex neurons integrate and transform encoded auditory information to guide sound-driven perceptual decisions.

Integrating sensory information over time is one of the fundamental attributes that is required for accurate perceptual decisions (1, 2). This process is supported by the transformation of stimulus representations into decision variables. In the case of auditory stimuli, prior to the formation of decision variables, the central representations of acoustic cues are gradually reconfigured along the auditory neuraxis. Thus, auditory neurons become more selective to contextually relevant acoustic features as one ascends the central pathway into the auditory cortex (3). Ultimately, individual acoustic components merge into auditory objects to guide perception (4). Similarly, primary visual cortex neurons are selective to the stimulus orientation (5, 6), whereas higher cortices are selective for more complex characteristics (7–9). A hierarchical progression of sensory information processing is also seen across the somatosensory ascending pathway where receptive fields grow more complex (10). These hierarchically transformed neural signals are ultimately decoded downstream of sensory cortices for stimulus-dependent decisions (4, 11–14).Studies in both nonhuman primates and rodents suggest that the parietal cortex integrates sensory inputs and transforms them into decision signals (15–19). The parietal cortex receives direct projections from primary or secondary sensory cortices (20, 21), has been causally implicated in the performance of perceptual decision-making tasks (22–25), and its activity typically reflects action selection (26, 27). Furthermore, parietal neurons gradually increase their spiking activity over time epochs that scale with the accumulation of sensory evidence (11, 28–31). Thus, while parietal cortex activity reflects decision variables, the manner in which relevant sensory stimuli are represented prior to this transformation remains uncertain.To dissociate encoding of stimuli from encoding of decision, we recorded neural activity from the parietal cortex while gerbils performed an auditory discrimination task (25), and again during passive listening sessions, using the same acoustic stimuli in the absence of behavioral decision. While some visual studies have explored visual selectivity of parietal cortex neurons under passive fixation conditions (32, 33), a direct comparison between the decoding of visual stimuli versus decision would require that eye fixation be controlled during stimulus presentation. In contrast, auditory tasks can be performed without the need to maintain head position during a trial, permitting us to directly compare the sound-driven responses of parietal cortex neurons during task engagement versus their responses to identical stimuli during passive listening. Thus, we predicted that if parietal cortex activity during task performance did not reflect the transition into decision-related variables, then all analyses of neural processing would be similar to those displayed during the passive listening condition. We found that during task performance, decoded parietal cortex population activity based on stimulus identity correlated with behavioral discrimination across similar timescales. Furthermore, principal component analysis (PCA) performed on parietal cortex responses revealed neural trajectories (i.e., the change in parietal cortex population activity over time) that demonstrated the temporal progression of low-dimensional encoding of acoustic information that transitioned to encoding of behavioral choices. During passive listening sessions, decoding performance from parietal cortex population activity based on stimulus identity was poorer than decoding during task performance, but scaled with stimulus duration. In addition, the PCA revealed neural trajectories that differentiated between each stimulus condition, but did not reflect a decision variable. Thus, the parietal cortex could accumulate auditory evidence for the purpose of forming a decision variable during task performance. Finally, our clustering analysis based on neuronal response properties suggest subpopulations of parietal neurons that may reflect separate temporal segments of individual trials during decision-making. We propose that the parietal cortex integrates and transforms bottom-up sensory information into decision variables during task performance.     

DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward

When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning. Rhinal cortex was injected with a DNA construct that significantly decreased D2 receptor ligand binding and temporarily produced the same profound learning deficit seen after ablation. However, unlike after ablation, the D2 receptor-targeted, DNA-treated monkeys recovered cue-related learning after 11-19 weeks. Injecting a DNA construct that decreased N-methyl-d-aspartate but not D2 receptor ligand binding did not interfere with learning associations between the cues and the schedules. A second D2 receptor-targeted DNA treatment administered after either recovery from a first D2 receptor-targeted DNA treatment (one monkey), after N-methyl-d-aspartate receptor-targeted DNA treatment (two monkeys), or after a vector control treatment (one monkey) also induced a learning deficit of similar duration. These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions.     

Neural circuitry in the regulation of adrenal corticosterone rhythmicity

Adrenal cortical secretion of glucocorticoids is an essential adaptive response of an organism to stress. Although the hypothalamic-pituitary-adrenal axis regulates the adrenal cortex via release of ACTH, there is strong evidence supporting a role for sympathetic innervation in modulating adrenal glucocorticoid secretion. The dissociation between changes in ACTH and glucocorticoids under non-stress and stress conditions has reinforced the concept that neural control of the adrenal cortex acts to modulate steroidogenic responses to circulating ACTH. A dual control of the adrenal cortex has been implicated in the prominent circadian rhythm in glucocorticoids. However, the central neural substrate for circadian changes in glucocorticoids that are mediated by peripheral neural innervation of the adrenal cortex has not been conclusively delineated. The hypothesis to be addressed is that neurons in the paraventricular nucleus of the hypothalamus receive input from the suprachiasmatic nucleus and project to sympathetic preganglionic neurons in the spinal cord to provide inhibitory and excitatory input to the adrenal cortex that drives the circadian rhythm. This review examines anatomical and physiological evidence that forms the basis for this putative neural circuit.