The Journal of neuroscience : the official journal of the Society for Neuroscience
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The present study investigated how pitch frequency, a perceptually relevant aspect of periodicity in natural human vocalizations, is encoded in Heschl's gyrus (HG), and how this information may be used to influence vocal pitch motor control. We recorded local field potentials from multicontact depth electrodes implanted in HG of 14 neurosurgical epilepsy patients as they vocalized vowel sounds and received brief (200 ms) pitch perturbations at 100 Cents in their auditory feedback. Event-related band power responses to vocalizations showed sustained frequency following responses that tracked voice fundamental frequency (F0) and were significantly enhanced in posteromedial HG during speaking compared with when subjects listened to the playback of their own voice. In addition to frequency following responses, a transient response component within the high gamma frequency band (75-150 Hz) was identified. When this response followed the onset of vocalization, the magnitude of the response was the same for the speaking and playback conditions. In contrast, when this response followed a pitch shift, its magnitude was significantly enhanced during speaking compared with playback. We also observed that, in anterolateral HG, the power of high gamma responses to pitch shifts correlated with the magnitude of compensatory vocal responses. These findings demonstrate a functional parcellation of HG with neural activity that encodes pitch in natural human voice, distinguishes between self-generated and passively heard vocalizations, detects discrepancies between the intended and heard vocalization, and contains information about the resulting behavioral vocal compensations in response to auditory feedback pitch perturbations. ⋯ The present study is a significant contribution to our understanding of sensor-motor mechanisms of vocal production and motor control. The findings demonstrate distinct functional parcellation of core and noncore areas within human auditory cortex on Heschl's gyrus that process natural human vocalizations and pitch perturbations in the auditory feedback. In addition, our data provide evidence for distinct roles of high gamma neural oscillations and frequency following responses for processing periodicity in human vocalizations during vocal production and motor control.
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Different subregions of the prefrontal cortex (PFC) contribute to the ability to respond flexibly to changes in reward contingencies, with the medial versus orbitofrontal cortex (OFC) subregions contributing differentially to processes such as set-shifting and reversal learning. To date, the manner in which these regions may facilitate reversal learning in situations involving reward uncertainty remains relatively unexplored. We investigated the involvement of five distinct regions of the rat OFC (lateral and medial) and medial PFC (prelimbic, infralimbic, and anterior cingulate) on probabilistic reversal learning wherein "correct" versus "incorrect" responses were rewarded on 80% and 20% of trials, respectively. Contingencies were reversed repeatedly within a session. In well trained rats, inactivation of the medial or lateral OFC induced dissociable impairments in performance (indexed by fewer reversals completed) when outcomes were probabilistic, but not when they were assured. Medial OFC inactivation impaired probabilistic learning during the first discrimination, increased perseverative responding and reduced sensitivity to positive and negative feedback, suggestive of a deficit in incorporating information about previous action outcomes to guide subsequent behavior. Lateral OFC inactivation preferentially impaired performance during reversal phases. In contrast, prelimbic inactivation caused an apparent improvement in performance by increasing the number of reversals completed. This was associated with enhanced sensitivity to recently rewarded actions and reduced sensitivity to negative feedback. Infralimbic inactivation had no effect, whereas the anterior cingulate appeared to play a permissive role in this form of reversal learning. These results clarify the dissociable contributions of different regions of the frontal lobes to probabilistic learning. ⋯ The ability to adjust behavior in response to changes involving uncertain or probabilistic reward contingencies is an essential survival skill that is impaired in a variety of psychiatric disorders. It is well established that different forms of cognitive flexibility are mediated by anatomically distinct regions of the frontal lobes when reinforcement contingencies are assured, however, less is known about the contribution of these regions to probabilistic reinforcement learning. Here we show that different regions of the orbitofrontal and medial prefrontal cortex make distinct contributions to probabilistic reversal learning. These findings provide novel information about the complex interplay between frontal lobe regions in mediating these processes and accordingly provide insight into possible pathophysiology that underlies impairments in cognitive flexibility observed in mental illnesses.
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Understanding the control of sleep-wake states by the basal forebrain (BF) poses a challenge due to the intermingled presence of cholinergic, GABAergic, and glutamatergic neurons. All three BF neuronal subtypes project to the cortex and are implicated in cortical arousal and sleep-wake control. Thus, nonspecific stimulation or inhibition studies do not reveal the roles of these different neuronal types. Recent studies using optogenetics have shown that "selective" stimulation of BF cholinergic neurons increases transitions between NREM sleep and wakefulness, implicating cholinergic projections to cortex in wake promotion. However, the interpretation of these optogenetic experiments is complicated by interactions that may occur within the BF. For instance, a recent in vitro study from our group found that cholinergic neurons strongly excite neighboring GABAergic neurons, including the subset of cortically projecting neurons, which contain the calcium-binding protein, parvalbumin (PV) (Yang et al., 2014). Thus, the wake-promoting effect of "selective" optogenetic stimulation of BF cholinergic neurons could be mediated by local excitation of GABA/PV or other non-cholinergic BF neurons. In this study, using a newly designed opto-dialysis probe to couple selective optical stimulation with simultaneous in vivo microdialysis, we demonstrated that optical stimulation of cholinergic neurons locally increased acetylcholine levels and increased wakefulness in mice. Surprisingly, the enhanced wakefulness caused by cholinergic stimulation was abolished by simultaneous reverse microdialysis of cholinergic receptor antagonists into BF. Thus, our data suggest that the wake-promoting effect of cholinergic stimulation requires local release of acetylcholine in the basal forebrain and activation of cortically projecting, non-cholinergic neurons, including the GABAergic/PV neurons. ⋯ Optogenetics is a revolutionary tool to assess the roles of particular groups of neurons in behavioral functions, such as control of sleep and wakefulness. However, the interpretation of optogenetic experiments requires knowledge of the effects of stimulation on local neurotransmitter levels and effects on neighboring neurons. Here, using a novel "opto-dialysis" probe to couple optogenetics and in vivo microdialysis, we report that optical stimulation of basal forebrain (BF) cholinergic neurons in mice increases local acetylcholine levels and wakefulness. Reverse microdialysis of cholinergic antagonists within BF prevents the wake-promoting effect. This important result challenges the prevailing dictum that BF cholinergic projections to cortex directly control wakefulness and illustrates the utility of "opto-dialysis" for dissecting the complex brain circuitry underlying behavior.
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Acetylcholine (ACh) is thought to facilitate cortical plasticity during memory formation and its release is regulated by the nucleus basalis magnocellularis (NBM). Questions remain regarding which neuronal circuits and neurotransmitters trigger activation or suppression of cortical cholinergic activity. During novel, but not familiar, taste consumption, there is a significant increase in ACh release in the insular cortex (IC), a highly relevant structure for taste learning. Here, we evaluate how GABA inhibition modulates cholinergic transmission and its involvement during taste novelty processing and familiar taste memory retrieval. Using saccharin as a taste stimulus in a taste preference paradigm, we examined the effects of injecting the GABAA receptor agonist muscimol or the GABAA receptor antagonist bicuculline into the IC or NBM during learning or retrieval of an appetitive taste memory on taste preference in male Sprague Dawley rats. GABAA receptor agonism and antagonism had opposite effects on cortical ACh levels in novel taste presentation versus familiar taste recognition and ACh levels were associated with the propensity to acquire or retrieve a taste memory. These results indicate that the pattern of cortical cholinergic and GABAergic neuroactivity during novel taste exposure is the opposite of that which occurs during familiar taste recognition and these differing neurotransmitter system states may enable different behavioral consequences. Divergences in ACh and GABA levels may produce differential alterations in excitatory and inhibitory neural processes within the cortex during acquisition and retrieval. ⋯ During learning and recall, several brain structures act together. This work demonstrates interactions between cortical cholinergic and GABAergic systems during taste learning and memory retrieval. We found that the neuroactivity pattern during novel taste exposure is opposite that which occurs during familiar taste recognition. GABAA receptors must be inactive during novel tasting to enable new memory formation, but must be active and inhibiting acetylcholine release in the cortex to allow memory retrieval. These findings indicate that GABA inhibition modulates cholinergic transmission and that cholinergic-GABAergic system interactions are important during the transition from novel to familiar memory.
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The ventrolateral periaqueductal gray (vlPAG) is a key structure in the descending pain modulatory circuit. Activation of the circuit occurs via disinhibition of GABAergic inputs onto vlPAG output neurons. In these studies, we tested the hypothesis that GABAergic inhibition is increased during persistent inflammation, dampening activation of the descending circuit from the vlPAG. Our results indicate that persistent inflammation induced by Complete Freund's adjuvant (CFA) modulates GABA signaling differently in male and female rats. CFA treatment results in increased presynaptic GABA release but decreased high-affinity tonic GABAA currents in female vlPAG neurons. These effects are not observed in males. The tonic currents in the vlPAG are dependent on GABA transporter activity and are modulated by agonists that activate GABAA receptors containing the δ subunit. The GABAA δ agonist THIP (gaboxadol) induced similar amplitude currents in naive and CFA-treated rats. In addition, a positive allosteric modulator of the GABAA δ subunit, DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide), increased tonic currents. These results indicate that GABAA δ receptors remain on the cell surface but are less active in CFA-treated female rats. In vivo behavior studies showed that morphine induced greater antinociception in CFA-treated females that was reversed with microinjections of DS2 directly into the vlPAG. DS2 did not affect morphine antinociception in naive or CFA-treated male rats. Together, these data indicate that sex-specific adaptations in GABAA receptor signaling modulate opioid analgesia in persistent inflammation. Antagonists of GABAA δ receptors may be a viable strategy for reducing pain associated with persistent inflammation, particularly in females. ⋯ These studies demonstrate that GABA signaling is modulated in the ventrolateral periaqueductal gray by persistent inflammation differently in female and male rats. Our results indicate that antagonists or negative allosteric modulators of GABAA δ receptors may be an effective strategy to alleviate chronic inflammatory pain and promote opioid antinociception, especially in females.