Explore the vast range of titles available.

Many fearful expectations are shaped by observation of aversive outcomes to others. Yet, the neurochemistry regulating social learning is unknown. Previous research has shown that during direct (Pavlovian) threat learning, information about personally experienced outcomes is regulated by the release of endogenous opioids, and activity within the amygdala and periaqueductal gray (PAG). Here we report that blockade of this opioidergic circuit enhances social threat learning through observation in humans involving activity within the amygdala, midline thalamus and the PAG. In particular, anticipatory responses to learned threat cues (CS) were associated with temporal dynamics in the PAG, coding the observed aversive outcomes to other (observational US). In addition, pharmacological challenge of the opioid receptor function is classified by distinct brain activity patterns during the expression of conditioned threats. Our results reveal an opioidergic circuit that codes the observed aversive outcomes to others into threat responses and long-term memory in the observer. Though humans often learn about negative outcomes from observing the response of others, the neurochemistry underlying this learning is unknown. Here, authors show that blocking opioid receptors enhances social threat learning and describe the brain regions underlying this effect.

Background: Electroacupuncture (EA) is currently one of the most popular acupuncture modalities. However, the continuous stimulation characteristic of EA treatment presents challenges to the use of conventional functional Magnetic Resonance Imaging (fMRI) approaches for the investigation of neural mechanisms mediating treatment response because of the requirement for brief and intermittent stimuli in event related or block designed task paradigms. A relatively new analysis method, functional connectivity fMRI (fcMRI), has great potential for studying continuous treatment modalities such as EA. In a previous study, we found that, compared with sham acupuncture, EA can significantly reduce Periaqueductal Gray (PAG) activity when subsequently evoked by experimental pain. Given the PAG's important role in mediating acupuncture analgesia, in this study we investigated functional connectivity with the area of the PAG we previously identified and how that connectivity was affected by genuine and sham EA. Results: Forty-eight subjects, who were randomly assigned to receive either genuine or sham EA paired with either a high or low expectancy manipulation, completed the study. Direct comparison of each treatment mode's functional connectivity revealed: significantly greater connectivity between the PAG, left posterior cingulate cortex (PCC), and precuneus for the contrast of genuine minus sham; significantly greater connectivity between the PAG and right anterior insula for the contrast of sham minus genuine; no significant differences in connectivity between different contrasts of the two expectancy levels. Conclusions: Our findings indicate the intrinsic functional connectivity changes among key brain regions in the pain matrix and default mode network during genuine EA compared with sham EA. We speculate that continuous genuine EA stimulation can modify the coupling of spontaneous activity in brain regions that play a role in modulating pain perception.

Abstract BACKGROUND: Deep brain stimulation (DBS) of subcortical brain areas such as the periaqueductal grey and subthalamic nucleus has been shown to alter cardiovascular autonomic performance. The supramedullary circuitry controlling respiratory airways is not well defined and has not been tested in humans. OBJECTIVE: To use direct electric stimulation via DBS macroelectrodes to test whether airway resistance could be manipulated by these areas in awake humans. METHODS: Thirty-seven patients with in-dwelling deep brain electrodes for movement disorders or chronic pain underwent spirometry according to the European Respiratory Society guidelines. Testing was performed randomly 3 times on stimulation and 3 times off stimulation; patients were blinded to the test. Thoracic diameter changes were measured by a circumferential pressure-sensitive thoracic band. Ten periaqueductal grey and 10 subthalamic nucleus patients were tested. To control for confounding pain and movement disorder relief, the sensory thalamus in 7 patients and globus pallidus interna in 10 patients, respectively, were also tested. RESULTS: Peak expiratory flow rate (PEFR) increased significantly with periaqueductal grey and subthalamic nucleus stimulation by up to 14% (P = .02 and .005, respectively, paired-samples Student t tests). Stimulation of control nuclei produced no significant PEFR change. Similarly, changes in thoracic diameter reflecting skeletal activity rather than airway caliber did not correlate with the improvement in PEFR. Forced expiratory volume in 1 second was unchanged by stimulation. CONCLUSION: DBS can improve PEFR in chronic pain and movement disorder patients. This finding provides insights into the neural modulation of respiratory performance and may explain some of the subjective benefits of DBS.

Mammalian sleep consists of distinct rapid eye movement (REM) and non-REM (NREM) states. The midbrain region ventrolateral periaqueductal gray (vlPAG) is known to be important for gating REM sleep, but the underlying neuronal mechanism is not well understood. Here, we show that activating vlPAG GABAergic neurons in mice suppresses the initiation and maintenance of REM sleep while consolidating NREM sleep, partly through their projection to the dorsolateral pons. Cell-type-specific recording and calcium imaging reveal that most vlPAG GABAergic neurons are strongly suppressed at REM sleep onset and activated at its termination. In addition to the rapid changes at brain state transitions, their activity decreases gradually between REM sleep and is reset by each REM episode in a duration-dependent manner, mirroring the accumulation and dissipation of REM sleep pressure. Thus, vlPAG GABAergic neurons powerfully gate REM sleep, and their firing rate modulation may contribute to the ultradian rhythm of REM/NREM alternation. The vlPAG in the midbrain is known to suppress REM sleep, but the precise neural correlates are not known. Here, the authors record the activity of vlPAG GABAergic neurons during the sleep–wake cycle and report fast changes at REM sleep transitions and slower changes that correlate with REM sleep pressure.

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this ‘survival circuit’ has been implicated in anxiety-related disorders. A combination of optogenetic, electrophysiological and neuroanatomical tracing methods defines midbrain periaqueductal grey circuits for specific defensive behaviours. Brain circuits choosing the response to threat A mouse perceiving a threat has a choice between two principal means of defence: active flight or a passive 'freeze'. Andreas Lüthi and colleagues have used a combination of optogenetic, electrophysiological and neuroanatomical tracing to identify the neural circuits underlying the control of these different strategies. They identify a pathway from the amygdala to the periaqueductal grey that not only mediates freezing, but also interacts with circuits mediating flight. Freezing is an evolutionarily conserved behaviour in many species, including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders.

Activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. Control of REM sleep Previous attempts to understand the contribution of specific brain regions to the promotion and maintenance of rapid eye movement (REM) sleep, the type of sleep during which most instances of dreaming occur, have mainly relied on transection or lesion-based studies. Here, Yang Dan and colleagues use optogenetics to demonstrate that activation of GABAergic neurons in the ventral medulla can reliably induce REM sleep and prolong the duration of REM episodes in mice. The ability to control REM sleep at a high temporal precision, as demonstrated in this study, should provide a useful tool for the study of its functions. Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams 1 , 2 , 3 . Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation 2 , and the neural circuits in the pons have since been studied extensively 4 , 5 , 6 , 7 , 8 . The medulla also contains neurons that are active during REM sleep 9 , 10 , 11 , 12 , 13 , but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REM max ), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here we have identified a circuit that reciprocally connects the ventral periaqueductal gray and dorsal raphe region with the central amygdala and that gates fear learning. We found that ventral periaqueductal gray and dorsal raphe dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation. Negative feedback from the central amygdala to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain dopaminergic circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as a critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders.

What individual differences in neural activity predict the future escalation of alcohol drinking from casual to compulsive? The neurobiological mechanisms that gate the transition from moderate to compulsive drinking remain poorly understood. We longitudinally tracked the development of compulsive drinking across a binge-drinking experience in male mice. Binge drinking unmasked individual differences, revealing latent traits in alcohol consumption and compulsive drinking despite equal prior exposure to alcohol. Distinct neural activity signatures of cortical neurons projecting to the brainstem before binge drinking predicted the ultimate emergence of compulsivity. Mimicry of activity patterns that predicted drinking phenotypes was sufficient to bidirectionally modulate drinking. Our results provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol drinking.

Itch is a distinct aversive sensation that elicits a strong urge to scratch. Despite recent advances in our understanding of the peripheral basis of itch, we know very little regarding how central neural circuits modulate acute and chronic itch processing. Here we establish the causal contributions of defined periaqueductal gray (PAG) neuronal populations in itch modulation in mice. Chemogenetic manipulations demonstrate bidirectional modulation of scratching by neurons in the PAG. Fiber photometry studies show that activity of GABAergic and glutamatergic neurons in the PAG is modulated in an opposing manner during chloroquine-evoked scratching. Furthermore, activation of PAG GABAergic neurons or inhibition of glutamatergic neurons resulted in attenuation of scratching in both acute and chronic pruritis. Surprisingly, PAG GABAergic neurons, but not glutamatergic neurons, may encode the aversive component of itch. Thus, the PAG represents a neuromodulatory hub that regulates both the sensory and affective aspects of acute and chronic itch. The supraspinal mechanisms involved in itch specific sensation are not well understood. Here the authors identify a subpopulation of neurons in the periaqueductal gray that modulate chronic itch in rodents

The authors describe cortical projections mediating the modulation of social behavior. Neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray play a critical role in the behavioral adaptation to social defeat in mice. The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.