Neuronal Population Encoding of Identity in Primate Prefrontal Cortex.

The ventrolateral prefrontal cortex (VLPFC) shows robust activation during the perception of faces and voices. However, little is known about what categorical features of social stimuli drive neural activity in this region. Since perception of identity and expression are critical social functions, we examined whether neural responses to naturalistic stimuli were driven by these two categorical features in the prefrontal cortex. We recorded single neurons in the VLPFC, while two male rhesus macaques (Macaca mulatta) viewed short audiovisual videos of unfamiliar conspecifics making expressions of aggressive, affiliative, and neutral valence. Of the 285 neurons responsive to the audiovisual stimuli, 111 neurons had a main effect (two-way ANOVA) of identity, expression, or their interaction in their stimulus-related firing rates; however, decoding of expression and identity using single-unit firing rates rendered poor accuracy. Interestingly, when decoding from pseudo-populations of recorded neurons, the accuracy for both expression and identity increased with population size, suggesting that the population transmitted information relevant to both variables. Principal components analysis of mean population activity across time revealed that population responses to the same identity followed similar trajectories in the response space, facilitating segregation from other identities. Our results suggest that identity is a critical feature of social stimuli that dictates the structure of population activity in the VLPFC, during the perception of vocalizations and their corresponding facial expressions. These findings enhance our understanding of the role of the VLPFC in social behavior.

Neural circuits in auditory and audiovisual memory.

Working memory is the ability to employ recently seen or heard stimuli and apply them to changing cognitive context. Although much is known about language processing and visual working memory, the neurobiological basis of auditory working memory is less clear. Historically, part of the problem has been the difficulty in obtaining a robust animal model to study auditory short-term memory. In recent years there has been neurophysiological and lesion studies indicating a cortical network involving both temporal and frontal cortices. Studies specifically targeting the role of the prefrontal cortex (PFC) in auditory working memory have suggested that dorsal and ventral prefrontal regions perform different roles during the processing of auditory mnemonic information, with the dorsolateral PFC performing similar functions for both auditory and visual working memory. In contrast, the ventrolateral PFC (VLPFC), which contains cells that respond robustly to auditory stimuli and that process both face and vocal stimuli may be an essential locus for both auditory and audiovisual working memory. These findings suggest a critical role for the VLPFC in the processing, integrating, and retaining of communication information. This article is part of a Special Issue entitled SI: Auditory working memory.

Timing of audiovisual inputs to the prefrontal cortex and multisensory integration.

A number of studies have demonstrated that the relative timing of audiovisual stimuli is especially important for multisensory integration of speech signals although the neuronal mechanisms underlying this complex behavior are unknown. Temporal coincidence and congruency are thought to underlie the successful merging of two intermodal stimuli into a coherent perceptual representation. It has been previously shown that single neurons in the non-human primate prefrontal cortex integrate face and vocalization information. However, these multisensory responses and the degree to which they depend on temporal coincidence have yet to be determined. In this study we analyzed the response latency of ventrolateral prefrontal (VLPFC) neurons to face, vocalization and combined face-vocalization stimuli and an offset (asynchronous) version of the face-vocalization stimulus. Our results indicate that for most prefrontal multisensory neurons, the response latency for the vocalization was the shortest, followed by the combined face-vocalization stimuli. The face stimulus had the longest onset response latency. When tested with a dynamic face-vocalization stimulus that had been temporally offset (asynchronous) one-third of multisensory cells in VLPFC demonstrated a change in response compared to the response to the natural, synchronous face-vocalization movie. Our results indicate that prefrontal neurons are sensitive to the temporal properties of audiovisual stimuli. A disruption in the temporal synchrony of an audiovisual signal which results in a change in the firing of communication related prefrontal neurons could underlie the loss in intelligibility which occurs with asynchronous speech stimuli.

Neurons responsive to face-view in the primate ventrolateral prefrontal cortex.

Studies have indicated that temporal and prefrontal brain regions process face and vocal information. Face-selective and vocalization-responsive neurons have been demonstrated in the ventrolateral prefrontal cortex (VLPFC) and some prefrontal cells preferentially respond to combinations of face and corresponding vocalizations. These studies suggest VLPFC in nonhuman primates may play a role in communication that is similar to the role of inferior frontal regions in human language processing. If VLPFC is involved in communication, information about a speaker's face including identity, face-view, gaze, and emotional expression might be encoded by prefrontal neurons. In the following study, we examined the effect of face-view in ventrolateral prefrontal neurons by testing cells with auditory, visual, and a set of human and monkey faces rotated through 0°, 30°, 60°, 90°, and -30°. Prefrontal neurons responded selectively to either the identity of the face presented (human or monkey) or to the specific view of the face/head, or to both identity and face-view. Neurons which were affected by the identity of the face most often showed an increase in firing in the second part of the stimulus period. Neurons that were selective for face-view typically preferred forward face-view stimuli (0° and 30° rotation). The neurons which were selective for forward face-view were also auditory responsive compared to other neurons which responded to other views or were unselective which were not auditory responsive. Our analysis showed that the human forward face (0°) was decoded better and also contained the most information relative to other face-views. Our findings confirm a role for VLPFC in the processing and integration of face and vocalization information and add to the growing body of evidence that the primate ventrolateral prefrontal cortex plays a prominent role in social communication and is an important model in understanding the cellular mechanisms of communication.

Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex.

'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory-prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.

Auditory belt and parabelt projections to the prefrontal cortex in the rhesus monkey.

Recent anatomical and electrophysiological studies have expanded our knowledge of the auditory cortical system in primates and have described its organization as a series of concentric circles with a central or primary auditory core, surrounded by a lateral and medial belt of secondary auditory cortex with a tertiary parabelt cortex just lateral to this belt. Because recent studies have shown that rostral and caudal belt and parabelt cortices have distinct patterns of connections and acoustic responsivity, we hypothesized that these divergent auditory regions might have distinct targets in the frontal lobe. We, therefore, placed discrete injections of wheat germ agglutinin-horseradish peroxidase or fluorescent retrograde tracers into the prefrontal cortex of macaque monkeys and analyzed the anterograde and retrograde labeling in the aforementioned auditory areas. Injections that included rostral and orbital prefrontal areas (10, 46 rostral, 12) labeled the rostral belt and parabelt most heavily, whereas injections including the caudal principal sulcus (area 46), periarcuate cortex (area 8a), and ventrolateral prefrontal cortex (area12vl) labeled the caudal belt and parabelt. Projections originating in the parabelt cortex were denser than those arising from the lateral or medial belt cortices in most cases. In addition, the anterior third of the superior temporal gyrus and the dorsal bank of the superior temporal sulcus were also labeled after prefrontal injections, confirming previous studies. The present topographical results suggest that acoustic information diverges into separate streams that target distinct rostral and caudal domains of the prefrontal cortex, which may serve different acoustic functions.

Topographic organization of medial pulvinar connections with the prefrontal cortex in the rhesus monkey.

The medial nucleus of the pulvinar complex (PM) has widespread connections with association cortex. We investigated the connections of the PM with the prefrontal cortex (PFC) in macaque monkeys, with tracers placed into the PM and the PFC, respectively. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) placed into the PM resulted in widespread anterograde terminal labeling in layers III and IV, and retrograde cellular labeling in layer VI of the PFC. Injections of tracers centered on the central/lateral PM resulted in labeling of dorsolateral and orbital regions, whereas injections centered on caudal, medial PM resulted in labeling of dorsomedial and medial PFC. Since injections of the PM included neighboring thalamic nuclei, retrograde tracers were placed into distinct cytoarchitectonic regions of the PFC and retrogradely labeled cells in the posterior thalamus were charted. The results of this series of tracer injections confirmed the results of thalamic injections. Injections placed into areas 8a, 12 (lateral and orbital), 45, 46 and 11, retrogradely labeled neurons in the central/lateral PM, while tracer injections placed into areas 9, 12 (lateral), 10 and 24, labeled medial PM. The connections of the PM with temporal, parietal, insular, and cingulate cortices were also examined. The central/lateral PM has reciprocal connections with posterior parietal areas 7a, 7ip, and 7b, insular cortex, caudal superior temporal sulcus (STS), caudal superior temporal gyrus (STG), and posterior cingulate, whereas medial PM is connected mainly with the anterior STS and STG, as well as the cingulate cortex and the amygdala. These connectional studies suggest that the central/ lateral and medial PM have divergent connections which may be the substrate for distinct functional circuits.

Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats.

The conditioning of fear responses to a simple acoustic stimulus (pure tone) paired with footshock can be mediated by the transmission of auditory information to the lateral nucleus of the amygdala from either the auditory thalamus or the auditory cortex. We examined the processing capacity of the thalamo-amygdala pathway by making lesions of the auditory cortex and testing the extent to which conditioned fear responses generalized to tones other than the one paired with footshock. Two studies were performed, one in an anatomically constrained computational model of the fear conditioning network and the other in rats. Stimulus generalization was unaffected in both. These findings support the validity of the model as an approach to studying the neural basis of conditioned fear learning, and in addition suggest that the thalamo-amygdala pathway, possibly by the use of population coding, is capable of performing at least crude stimulus discriminations.

Extinction of emotional learning: contribution of medial prefrontal cortex.

Stimuli associated with painful or otherwise unpleasant events acquire aversive emotional properties in animals and humans. Subsequent presentation of the stimulus alone (in the absence of the unpleasant event) leads to the eventual extinction of the aversive reaction. Although the neural basis of emotional learning has been studied extensively, considerably less is known about the neural basis of emotional extinction. In the present study, we show that the medial prefrontal cortex plays an important role in the regulation of fear extinction in rats, a finding that may help elucidate the mechanisms and, possibly, the treatment of disorders of uncontrolled fear, such as anxiety, phobic, panic and posttraumatic stress disorders in humans.

Organization of rodent auditory cortex: anterograde transport of PHA-L from MGv to temporal neocortex.

In the present study we analyzed the organization of the thalamocortical projections of the specific auditory relay nucleus of the thalamus, the ventral division of the medial geniculate body (MGv), using the anterograde axonal tracer Phaseolus vulgaris leucoagglutinin. All injections of MGv produced dense labeling of axonal fibers in temporal cortex. In all cases, labeled axons were predominantly concentrated in cortical layers III and IV and, to a lesser extent, at the junction of layers V and VI. Injections confined to the medial regions of MGv, and specifically to the ovoid nucleus of MGv (OV, pars ovoidea), resulted in anterograde labeling of TE1, with minor labeling of the ventral quarter of TE1, designated subarea TE1v. Injections placed in lateral regions of MGv and occupying the lateral ventral subnucleus (LV), or injections in the mediolateral center of MGv and occupying parts of LV and OV, also resulted in labeling of area TE1 and minor labeling of TE1v. However, these injections also produced labeling in areas TE2 and TE3. Thus, area TE1 (excluding subarea TE1v) receives heavy projections from all aspects of MGv and appears to be the core target of MGv. While regions of MGv also project to surrounding cortical belt areas, these projections tend to be lighter and to vary depending on the region of MGv examined. These results, together with other connectional findings, and cytoarchitectonic and physiological studies, suggest that TE1 (possibly excluding subarea TE1v) is the primary auditory cortex in the rat.

Information cascade from primary auditory cortex to the amygdala: corticocortical and corticoamygdaloid projections of temporal cortex in the rat.

Corticocortical and corticoamygdaloid connections of temporal cortext and perirhinal cortex (PRh) were examined in the rat with the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L). Iontophoretic injections of PHA-L into area TE1 resulted in columnar axonal terminations in surrounding and contralateral regions of temporal neocortex and in the striatum, but not in the amygdala. Within temporal neocortex, labeled fibers were present locally in adjacent regions of TE1, as well as in TE2d, TE1v, TE3v, and TE2c. Injection of cortical areas TE1v, TE3v, and TE2c, which received projections from TE1, or injections of perirhinal periallocortex, which received projections from TE1v, TE2v, and TE3v, resulted in projections to the amygdala. The pattern of corticocortical and corticoamygdaloid projections differed among the divisions of auditory cortex. TE1 exhibited extensive ipsilateral and contralateral projections to temporal cortical regions and no projections to the amygdala. In contrast, areas of temporal neocortex ventral and posterior to TE1, including TE1v, TE3v, TE2c, and PRh, had more limited ipsi- and contralateral corticocortical projections but had an increased connectivity with the subcortical forebrain, especially the lateral nucleus of the amygdala (AL). There was a topographic organization to the AL afferents. The dorsal subdivision of AL received projections from TE1v, TE3v, TE2c, and PRh, while the ventrolateral division received projections from TE3v, TE2c, and PRh. The ventromedial division received projections only from PRh, which, unlike other temporal cortical areas, also projected to the basolateral and basomedial nuclei of the amygdala. These findings define the complete sequence of connections linking primary auditory cortex with the amygdala in the rat. In addition, the findings indicate that the ventral portion of TE1, designated TE1v, has connections that distinguish it from dorsal TE1, namely, dense projections to AL and a diminished number of corticocortical projections ipsilaterally and contralaterally. Finally, the results suggest a topographic organization to the cortical terminations within the amygdala.

Somatosensory and auditory convergence in the lateral nucleus of the amygdala.

Previous studies have shown that the lateral nucleus of the amygdala (AL) is essential in auditory fear conditioning and that neurons in the AL respond to auditory stimuli. The goals of the present study were to determine whether neurons in the AL are also responsive to somatosensory stimuli and, if so, whether single neurons in the AL respond to both auditory and somatosensory stimulation. Single-unit activity was recorded in the AL in anesthetized rats during the presentation of acoustic (clicks) and somatosensory (footshock) stimuli. Neurons in the dorsal subdivision of the AL responded to both somatosensory and auditory stimuli, whereas neurons in the ventrolateral AL responded only to somatosensory stimuli and neurons in the ventromedial AL did not respond to either stimuli. These findings indicate that the dorsal AL is a site of auditory and somatosensory convergence and may therefore be a locus of convergence of conditioned and unconditioned stimuli in auditory fear conditioning.

Equipotentiality of thalamo-amygdala and thalamo-cortico-amygdala circuits in auditory fear conditioning.

The goal of the present study was to examine the contribution of thalamo-amygdala and thalamo-cortico-amygdala projections to fear conditioning. Lesions were used to destroy either the thalamo-cortico-amygdala projection, the thalamo-amygdala projection, or both projections, and the effects of such lesions on the acquisition of conditioned fear responses (changes in arterial pressure and freezing behavior) to a tone paired with footshock were measured. In each group of animals examined, a large lesion of the acoustic thalamus, including all nuclei of the medial geniculate body and adjacent portions of the posterior thalamus, was made on one side of the brain to block auditory transmission to the forebrain at the level of the thalamus on that side. In this way, experimental lesions could be made on the contralateral side of the brain. Thus, animals with thalamo-amygdala pathway lesions received a large lesion of the acoustic thalamus on one side. Contralaterally, only the nuclei that project to the amygdala (the medial division of the medial geniculate body, the posterior intralaminar nucleus, and the suprageniculate nucleus) were selectively destroyed, leaving much of the thalamo-cortico-amygdala projection intact. For thalamo-cortico-amygdala pathway lesions, the acoustic thalamus was destroyed on one side and temporal and perirhinal cortices were ablated contralaterally. In these animals, thalamo-amygdala projections were intact on the side of the cortical lesion. Destruction of either pathway alone had no effect on auditory fear conditioning. However, combined lesions of the two sensory pathways disrupted conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral destruction of neocortical and perirhinal projection targets of the acoustic thalamus does not disrupt auditory fear conditioning.

The present study examined whether complete bilateral destruction of auditory cortex would interfere with auditory fear conditioning in rats. Complete destruction of auditory cortex required lesions of temporal neocortical and perirhinal periallocortical areas. Fear conditioning was assessed by measuring freezing and arterial pressure responses elicited by an acoustic stimulus after pairing with footshock. Animals with complete bilateral lesions of auditory cortex showed conditioned arterial pressure and freezing responses comparable to those of unoperated controls. In contrast, bilateral destruction of the acoustic thalamus interfered with the conditioning of both responses. These results demonstrate that the auditory cortex is not required for the conditioning of fear responses to simple acoustic stimuli and add to the growing body of evidence that fear conditioning can be mediated by subcortical (amygdaloid) projections of the acoustic thalamus.

Overlapping projections to the amygdala and striatum from auditory processing areas of the thalamus and cortex.

The purpose of this study was to advance our understanding of the anatomical organization of sensory projections to the amygdala, and specifically to identify potential interactions within the amygdala between thalamic and cortical sensory projections of a single sensory modality. Thus, interconnections between the amygdala and acoustic processing areas of the thalamus and cortex were examined in the rat using WGA-HRP as an anterograde and a retrograde axonal tracer. Injections placed in medial aspects of the medial geniculate body (MGB) produced anterograde transport to the lateral nucleus of the amygdala and to adjacent areas of the striatum. Injections of primary auditory cortex (TE1) produced no transport to amygdala. In contrast, injections ventral to TE1 involving TE3 and perirhinal periallocortex (PRh) produced anterograde transport in the subcortical forebrain that was indistinguishable from that produced by the MGB injections. The TE3 and PRh injections also resulted in retrograde transport to primary auditory cortex and to MGB, thus confirming the involvement of these ventral cortical areas in auditory functions. Injections of the lateral nucleus of the amygdala resulted in retrograde transport back to the medial areas of MGB and to temporal cortical areas PRh, TE3, and the ventral most part of TE1. Thus, auditory processing regions of the thalamus and cortex give rise to overlapping (possibly convergent) projections to the lateral nucleus of the amygdala. These projections may allow diverse auditory signals to act on common ensembles of amygdaloid neurons and may therefore play a role in the integration of sensory messages leading to emotional reactions.

The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning.

Previous work has implicated projections from the acoustic thalamus to the amygdala in the classical conditioning of emotional responses to auditory stimuli. The purpose of the present studies was to determine whether the lateral amygdaloid nucleus (AL), which is a major subcortical target of projections from the acoustic thalamus, might be the sensory interface of the amygdala in emotional conditioning. Lesions were placed in AL of rats and the effects on emotional conditioning were examined. Lesions of AL, but not lesions of the striatum above or the cortex adjacent to the AL, interfered with emotional conditioning. Lesions that only partially destroyed AL or lesions placed too ventrally that completely missed AL had no effect. AL lesions did not affect the responses elicited following nonassociative (random) training. AL is thus an essential link in the circuitry through which auditory stimuli are endowed with affective properties and may function as the sensory interface of the amygdala during emotional learning.

Involvement of cortical and thalamic auditory regions in retention of differential bradycardiac conditioning to acoustic conditioned stimuli in rabbits.

Our previous findings indicate that lesions in the medial division of the medial geniculate nucleus (mMGN) prevent the acquisition of differential conditioning of bradycardia to acoustic stimuli in rabbits. In the present experiment, the effect of lesions in mMGN on retention of differential bradycardiac conditioning was examined. In addition, the possible involvement of auditory cortex in differential conditioning was investigated. Electrodes were chronically implanted in mMGN, the ventral division of the medial geniculate nucleus (vMGN), or auditory cortex. After 7 days of recovery, animals received one differential Pavlovian conditioning session. At the end of the session, lesions were produced through the implanted electrodes. All animals demonstrated differential bradycardiac conditioning during the prelesion session. Animals with vMGN lesions also demonstrated differential conditioning during the postlesion session. However, mMGN and auditory cortex lesion animals failed to demonstrate differential conditioning during the postlesion session due to an increased response magnitude to the unpaired tone (CS-). These data support the hypothesis that mMGN plays a role in differential conditioning of bradycardia to tonal stimuli. In addition, these findings suggest that a possible corticothalamic pathway may be involved in the inhibition of the response to the CS-.

Ibotenic acid lesions in the medial geniculate region prevent the acquisition of differential Pavlovian conditioning of bradycardia to acoustic stimuli in rabbits.

The present study examined the effect of ibotenic acid lesions in the medial portion of the medial geniculate nucleus (mMGN) on differential heart rate (HR) conditioning to acoustic stimuli in rabbits. Lesions in mMGN prevented the acquisition of differential HR conditioned responses but not bradycardiac responses to the conditioned stimuli. The data suggest that cells in this region play an important role in the discriminative component of HR conditioning.