Extensive functional connectivity between brain areas implicated in mental imagery production and phobic fear during both emotional and neutral mental imagery.

Mental imagery is used by most people in their day-to-day cognition, for example, in planning, daydreaming, or remembering. Importantly, mental imagery has a powerful influence on emotion and is critically involved in many mental disorders. Thus, understanding the link between mental imagery and emotion is of clinical interest. For example, exposure therapy can be successfully conducted using mental imagery of fear-provoking stimuli, i.e., imaginal exposure. In this vein, accumulating evidence shows that mental imagery of a fearful stimulus produces a similar physiological and neural response as actual perception of the stimulus. Alas, knowledge of the neural processes underlying the link between mental imagery and emotion is limited. Functional magnetic resonance imaging data from a previous study on imaginal exposure (N = 30) was used to examine the functional connectivity during the production of phobic and neutral mental imagery. Regions of interest were selected from meta-analyses on brain regions consistently recruited during mental imagery production and phobic fear, respectively. Results showed that these regions were positively correlated during both phobic and neutral mental imagery production. Very few differences in functional connectivity between phobic and neutral imagery were found. Specifically, weaker functional connectivity between the supplemental motor area and a region including parts of the left insula and inferior frontal gyrus was observed during phobic (vs neutral) imagery. In conclusion, our findings suggest that brain regions previously implicated in mental imagery production and phobic fear are highly interconnected during the production of both phobic and neutral imagery.

A dedicated hypothalamic oxytocin circuit controls aversive social learning.

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.

Mindfulness training and exercise differentially impact fear extinction neurocircuitry.

BACKGROUND: The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated the impact of mindfulness training on brain mechanisms associated with fear-extinction learning, compared to an exercise-based program. METHODS: We investigated BOLD activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n = 49) or exercise-based stress management education program (n = 27). RESULTS: The groups exhibited similar reductions in stress, but the MBSR group was uniquely associated with enhanced activation of salience network nodes and increased hippocampal engagement. CONCLUSIONS: Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli, which in turn facilitates decreased aversive subjective responses and enhanced reappraisal of the memory.

Brn3b regulates the formation of fear-related midbrain circuits and defensive responses to visual threat.

Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here, we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also down-regulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.

Subcortico-amygdala pathway processes innate and learned threats.

Behavioral flexibility and timely reactions to salient stimuli are essential for survival. The subcortical thalamic-basolateral amygdala (BLA) pathway serves as a shortcut for salient stimuli ensuring rapid processing. Here, we show that BLA neuronal and thalamic axonal activity in mice mirror the defensive behavior evoked by an innate visual threat as well as an auditory learned threat. Importantly, perturbing this pathway compromises defensive responses to both forms of threats, in that animals fail to switch from exploratory to defensive behavior. Despite the shared pathway between the two forms of threat processing, we observed noticeable differences. Blocking ß-adrenergic receptors impairs the defensive response to the innate but not the learned threats. This reduced defensive response, surprisingly, is reflected in the suppression of the activity exclusively in the BLA as the thalamic input response remains intact. Our side-by-side examination highlights the similarities and differences between innate and learned threat-processing, thus providing new fundamental insights.

Natural antioxidant formula ameliorates lipopolysaccharide-induced impairment of hippocampal neurogenesis and contextual fear memory through suppression of neuroinflammation in rats.

This study investigated the ameliorating effects of a natural antioxidant formula (NAF) consisting of Ginkgo biloba leaf extract, docosahexaenoic acid/eicosapentaenoic acid, ferulic acid, flaxseed oil, vitamin E, and vitamin B12 on a lipopolysaccharide (LPS)-induced cognitive dysfunction model in rats. Six-week-old rats received a diet containing 0.5% (w/w) NAF for 38 days from Day 1, and LPS (1 mg/kg body weight) was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased interleukin-1ß and tumor necrosis factor-α in the hippocampus and cerebral cortex and the numbers of M1-type microglia/macrophages and GFAP+ reactive astrocytes in the hilus of the hippocampal dentate gyrus. NAF treatment decreased brain proinflammatory cytokine levels and increased the number of M2-type microglia/macrophages. During Days 34-38, LPS alone impaired fear memory acquisition and the extinction learning process, and NAF facilitated fear extinction learning. On Day 38, LPS alone decreased the number of type-3 neural progenitor cells in the hippocampal neurogenic niche, and NAF restored the number of type-3 neural progenitor cells and increased the numbers of both immature granule cells in the neurogenic niche and reelin+ hilar interneurons. Thus, NAF exhibited anti-inflammatory effects and ameliorated LPS-induced adverse effects on hippocampal neurogenesis and fear memory learning, possibly through amplification of reelin signaling by hilar interneurons. These results suggest that neuroinflammation is a key factor in the development of LPS-induced impairment of fear memory learning, and supplementation with NAF in the present study helped to prevent hippocampal neurogenesis and disruptive neurobehaviors caused by neuroinflammation.

Paraventricular Thalamus Dynamically Modulates Aversive Memory via Tuning Prefrontal Inhibitory Circuitry.

The impact of stress on the formation and expression of memory is well studied, especially on the contributions of stress hormones. But how stress affects brain circuitry dynamically to modulate memory is far less understood. Here, we used male C57BL6/J mice in an auditory fear conditioning as a model system to examine this question and focused on the impact of stress on dorsomedial prefrontal cortex (dmPFC) neurons which play an important role in probabilistic fear memory. We found that paraventricular thalamus (PVT) neurons are robustly activated by acute restraining stress. Elevated PVT activity during probabilistic fear memory expression increases spiking in the dmPFC somatostatin neurons which in turn suppresses spiking of dmPFC parvalbumin (PV) neurons, and reverts the usual low fear responses associated with probabilistic fear memory to high fear. This dynamic and reversible modulation allows the original memory to be preserved and modulated during memory expression. In contrast, elevated PVT activity during fear conditioning impairs synaptic modifications in the dmPFC PV-neurons and abolishes the formation of probabilistic fear memory. Thus, PVT functions as a stress sensor to modulate the formation and expression of aversive memory by tuning inhibitory functions in the prefrontal circuitry.SIGNIFICANCE STATEMENT The impact of stress on cognitive functions, such as memory and executive functions, are well documented especially on the impact by stress hormone. However, the contributions of brain circuitry are far less understood. Here, we show that a circuitry-based mechanism can dynamically modulate memory formation and expression, namely, higher stress-induced activity in paraventricular thalamus (PVT) impairs the formation and expression of probabilistic fear memory by elevating the activity of somatostatin-neurons to suppress spiking in dorsomedial prefrontal parvalbumin (PV) neurons. This stress impact on memory via dynamic tuning of prefrontal inhibition preserves the formed memory but enables a dynamic expression of memory. These findings have implications for better stress coping strategies as well as treatment options including better drug targets/mechanisms.

Characterization of ventromedial hypothalamus activity during exposure to innate and conditioned threats.

In the face of imminent predatory danger, animals quickly detect the threat and mobilize key survival defensive actions, such as escape and freezing. The dorsomedial portion of the ventromedial hypothalamus (VMH) is a central node in innate and conditioned predator-induced defensive behaviours. Prior studies have shown that activity of steroidogenic factor 1 (sf1)-expressing VMH cells is necessary for such defensive behaviours. However, sf1-VMH neural activity during exposure to predatory threats has not been well characterized. Here, we use single-cell recordings of calcium transients from VMH cells in male and female mice. We show this region is activated by threat proximity and that it encodes future occurrence of escape but not freezing. Our data also show that VMH cells encoded proximity of an innate predatory threat but not a fear-conditioned shock grid. Furthermore, chemogenetic activation of the VMH increases avoidance of innate threats, such as open spaces and a live predator. This manipulation also increased freezing towards the predator, without altering defensive behaviours induced by a shock grid. Lastly, we show that optogenetic VMH activation recruited a broad swath of regions, suggestive of widespread changes in neural defensive state. Taken together, these data reveal the neural dynamics of the VMH during predator exposure and further highlight its role as a critical component of the hypothalamic predator defense system.

Fear in the mind's eye: the neural correlates of differential fear acquisition to imagined conditioned stimuli.

Mental imagery is involved in both the expression and treatment of fear-related disorders such as anxiety and post-traumatic stress disorder. However, the neural correlates associated with the acquisition and generalization of differential fear conditioning to imagined conditioned stimuli are relatively unknown. In this study, healthy human participants (n = 27) acquired differential fear conditioning to imagined conditioned stimuli paired with a physical unconditioned stimulus (i.e. mild shock), as measured via self-reported fear, the skin conductance response and significant right anterior insula (aIn) activation. Multivoxel pattern analysis cross-classification also demonstrated that the pattern of activity in the right aIn during imagery acquisition was quantifiably similar to the pattern produced by standard visual acquisition. Additionally, mental imagery was associated with significant differential fear generalization. Fear conditioning acquired to imagined stimuli generalized to viewing those same stimuli as measured with self-reported fear and right aIn activity, and likewise fear conditioning to visual stimuli was associated with significant generalized differential self-reported fear and right aIn activity when imagining those stimuli. Together, the study provides a novel understanding of the neural mechanisms associated with the acquisition of differential fear conditioning to imagined stimuli and that of the relationship between imagery and emotion more generally.

Extracellular zinc regulates contextual fear memory formation in male rats through MMP-BDNF-TrkB pathway in dorsal hippocampus and basolateral amygdala.

Large amount of zinc (100 µM even up to 300 µM) is released from the nerve terminals in response to high frequency neuronal stimulation in certain brain regions including hippocampus and amygdala. However, its precise pharmacological effect is poorly understood. Here, we investigated the role of extracellular zinc (endogenous zinc) and exogenous zinc in memory formation using contextual fear conditioning (CFC) model. Male Sprague Dawley rats were trained for fear conditioning followed by in vivo microdialysis for collection of microdialysate samples from CA1 and CA3 regions of hippocampus and basolateral amygdala (BLA). Extracellular zinc chelator CaEDTA, BDNF scavenger TrkB-Fc, exogenous 7,8-DHF and matrix metalloproteinases (MMP) inhibitor were infused into the CA1 and CA3 regions of hippocampus and BLA after CFC. Different doses of exogenous zinc hydroaspartate were administered intraperitoneally immediately after CFC. We found that CFC increased the level of extracellular zinc in the hippocampus and BLA. Infusing the CaEDTA, TrkB-Fc and MMP inhibitor into the CA1 and CA3 regions of hippocampus and BLA disrupted the fear memory formation. Furthermore, administration of TrKB agonist 7,8-DHF reversed the inhibitory effect of CaEDTA on fear memory formation, suggesting that extracellular zinc may regulate fear memory formation via the BDNF-TrKB pathway. We also found that high dose of exogenous zinc hydroaspartate supplementation increased extracellular zinc levels in brain and enhanced fear memory formation. Altogether, these findings indicate that extracellular zinc may participate in formation of contextual fear memory through MMP-BDNF-TrkB pathway in the hippocampus and BLA.

Expanding the canon: An inclusive neurobiology of thalamic and subthalamic fear circuits.

Appropriate expression of fear in the face of threats in the environment is essential for survival. The sustained expression of fear in the absence of threat signals is a central pathological feature of trauma- and anxiety-related disorders. Our understanding of the neural circuitry that controls fear inhibition coalesces around the amygdala, hippocampus, and prefrontal cortex. By discussing thalamic and sub-thalamic influences on fear-related learning and expression in this review, we suggest a more inclusive neurobiological framework that expands our canonical view of fear. First, we visit how fear-related learning and expression is influenced by the aforementioned canonical brain regions. Next, we review emerging data that shed light on new roles for thalamic and subthalamic nuclei in fear-related learning and expression. Then, we highlight how these neuroanatomical hubs can modulate fear via integration of sensory and salient stimuli, gating information flow and calibrating behavioral responses, as well as maintaining and updating memory representations. Finally, we propose that the presence of this thalamic and sub-thalamic neuroanatomy in parallel with the tripartite prefrontal cortex-amygdala-hippocampus circuit allows for dynamic modulation of information based on interoceptive and exteroceptive signals. This article is part of the Special Issue on "Fear, Anxiety and PTSD".

Negative emotion-conditioned prepulse induces the attentional enhancement of prepulse inhibition in humans.

Prepulse inhibition (PPI) is a reduction of the acoustic startle reflex (ASR) when the startling stimulus is preceded by a weaker and non-startling stimulus (i.e., prepulse). Previous studies have revealed that PPI can be top-down modulated by selective attention to the fear-conditioned prepulse in animals. However, few researchers have tested this assumption in humans. Thus, in this study, the negative emotional-conditioned prepulse (CS+) was used to explore whether it could improve participants' attention, and further improve the PPI. The results showed that the CS+ prepulse increased the PPI only in females, PPI produced by CS+ prepulse was larger in females than in males, and the perceptual spatial attention further improved the PPI in both females and males. The results suggested that the PPI was affected by emotional, perceptual spatial attention, and sex. These findings highlight an additional method to measure top-down attentional regulation of PPI in humans. Which may offer a useful route to enhance the diagnosis of affective disorders, such as anxiety, depression, and post-traumatic stress disorder.

Optogenetic stimulation of infralimbic cortex projections to the paraventricular thalamus attenuates context-induced renewal.

Contexts associated with prior reinforcement can renew extinguished conditioned responding. The prelimbic (PL) and infralimbic (IL) cortices are thought to mediate the expression and suppression of conditioned responding, respectively. Evidence suggests that PL inputs to the paraventricular nucleus of the thalamus (PVT) drive the expression of cue-induced reinstatement of drug seeking and that IL inputs to the PVT mediate fear extinction retrieval. However, the role of these projections in renewal of appetitive Pavlovian conditioned responding is unknown. We trained male and female Long-Evans rats to associate a conditioned stimulus (CS; 10 s white noise) with delivery of a 10% sucrose unconditioned stimulus (US; .2 ml/CS) to a fluid port in a distinct context (Context A). We then extinguished responding by presenting the CS without the US in a different context (Context B). At test, rats were returned to Context A, and optogenetic stimulation was delivered to either the IL-to-PVT or PL-to-PVT pathway during CS presentations. Optically stimulating the IL-to-PVT, but not the PL-to-PVT pathway, attenuated ABA renewal of CS port entries, and this effect was similar in males and females. Further, rats self-administered optical stimulation of the IL-to-PVT but not the PL-to-PVT pathway suggesting that activation of the IL-to-PVT pathway is reinforcing. The effectiveness of optical stimulation parameters to activate neurons in the IL, PL and PVT was confirmed using Fos immunohistochemistry. These findings provide evidence for novel neural mechanisms in renewal of responding to a sucrose-predictive CS, as well as more generally in contextual processing and appetitive associative learning.

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus.

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Effects of social hierarchy on innate fear­induced panic responses.

Studies have previously demonstrated a relationship between social status and anxiety disorders such as panic disorder. Repeated episodes of panic attacks do not occur in combination with an actual fear stimulus or stressor. However, social ranking modulates the perception of the social signals of a threat or stressor. The hypothalamic nuclei are well­known for their role in the elaboration of fear­induced reactions. The dorsomedial hypothalamus (DMH) and the ventromedial hypothalamic (VMH) nuclei are hypothalamic subnuclei involved in the processing of threatening stimuli­evoked aversive response and innate fear development. These structures are also located in the medial amygdala­hypothalamus­brainstem circuit that modulates innate fear­induced defensive behaviors. This work aimed to investigate the relationship between social hierarchy and innate fear­induced panic­like responses in male rats. In our study, the dominance tube test was used to determine the social hierarchy. Then, DMH/VMH nuclei were unilaterally implanted with a guide cannula. After intra­DMH/VMH injection of bicuculline (GABAA receptor antagonist), both innate fear induction and differences in dominant/subordinate rats were evaluated by the open field test. Intra­DMH/VMH bicuculline increased the frequency of defensive immobility, forward escape movements, and crossing behaviors, as well as the duration of defensive immobility and forward escape movements in dominant rats. Subordinate rats showed a higher frequency of defensive attention, defensive immobility, and crossing than dominant rats. Additionally, dominant rats demonstrated a lower duration of defensive attention and defensive immobility than subordinate rats. Dominant rats seemed to adopt a form of innate­fear characterized by increased proactivity with the environment. In contrast, subordinate rats exhibited a reactive form of innate­fear characterized by passivity and freezing.

Fear in the Theater of the Mind: Differential Fear Conditioning With Imagined Stimuli.

Many symptoms of anxiety and posttraumatic stress disorder are elicited by fearful mental imagery. Yet little is known about how visual imagery of conditioned stimuli (CSs) affects the acquisition of differential fear conditioning. Across three experiments with younger human adults (Experiment 1: n = 33, Experiment 2: n = 27, Experiment 3: n = 26), we observed that participants acquired differential fear conditioning to both viewed and imagined percepts serving as the CSs, as measured via self-reported fear and skin conductance responses. Additionally, this differential conditioning generalized across CS-percept modalities such that differential conditioning acquired in response to visual percepts generalized to the corresponding imagined percepts and vice versa. This is novel evidence that perceived and imagined stimuli engage learning processes in very similar ways and is consistent with the theory that mental imagery is depictive and recruits neural resources shared with visual perception. Our findings also provide new insight into the mechanisms of anxiety and related disorders.

Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

Neuropeptide S Encodes Stimulus Salience in the Paraventricular Thalamus.

Evaluation of stimulus salience is critical for any higher organism, as it allows for prioritizing of vital information, preparation of responses, and formation of valuable memory. The paraventricular nucleus of the thalamus (PVT) has recently been identified as an integrator of stimulus salience but the neurochemical basis and afferent input regarding salience signaling have remained elusive. Here we report that neuropeptide S (NPS) signaling in the PVT is necessary for stimulus salience encoding, including aversive, neutral and reinforcing sensory input. Taking advantage of a striking deficit of both NPS receptor (NPSR1) and NPS precursor knockout mice in fear extinction or novel object memory formation, we demonstrate that intra-PVT injections of NPS can rescue the phenotype in NPS precursor knockout mice by increasing the salience of otherwise low-intensity stimuli, while intra-PVT injections of NPSR1 antagonist in wild type mice partially replicates the knockout phenotype. The PVT appears to provide stimulus salience encoding in a dose- and NPS-dependent manner. PVT NPSR1 neurons recruit the nucleus accumbens shell and structures in the prefrontal cortex and amygdala, which were previously linked to the brain salience network. Overall, these results demonstrate that stimulus salience encoding is critically associated with NPS activity in the PVT.

Perceptual spatial position induces the attentional enhancement of prepulse inhibition and its neural mechanism.

Prepulse inhibition (PPI) is a sensorimotor gating process that reduces the startling response when a weaker sensory stimulus precedes a sudden startling stimulus. Perceptual spatial separation (PSS) between the prepulse and the background noise was found to enhance PPI compared to perceptual spatial co-location (PSC). However, little is known about the perceptual characteristics of prepulses in the PSS that induce more inhibition of the startling response and the associated neural mechanism. The dorsocentral striatum (DCS) was the convergence of spatial information from the cortical and thalamic circuits. Our study investigated whether the perceptual spatial position of prepulses induced spatial attentional modulation of PPI. In addition, whether the DCS was involved in spatial attentional modulation's neural circuits of PPI. In our study, the relative perceptual image positions of the prepulse and masker were controlled by the playback time difference between the two loudspeakers, i.e., PSS and PSC. The specific spatial attention of the prepulse was conditioned by foot shock. The results revealed that PPI was generally enhanced after fear conditioning/conditioning-control manipulation across all rats. Further enhancement of PPI in the PSS condition occurred only in the fear conditioning position, not in the conditioning-control position. We first found that PPI did not show specific spatial enhancement in the drug-blocking bilateral DCS rats with 2 mM kynurenic acid. These results demonstrated that the perceptual spatial position modulated the spatial attention of prepulse and improved PPI. DCS was involved in the attentional modulation neural circuits of PPI and processed spatial information of prepulse.

Bifocal emotion regulation through acupoint tapping in fear of flying.

Very few studies have investigated the neural underpinnings of bifocal-multisensory interventions such as acupoint tapping (tapping) despite their well-documented efficacy. The present study aims to investigate the neural and behavioral responses to tapping during the perception of phobic and generally fear-inducing stimulation in a group of participants with fear of flying. We studied 29 flight-phobic participants who were exposed to phobia-related, fear-inducing and neutral stimulation while undergoing fMRI and a bifocal-multisensory intervention session consisting of tapping plus cognitive restructuring in a within-subject design. During tapping we found an up-regulation of neural activation in the amygdala, and a down-regulation in the hippocampus and temporal pole. These effects were different from automatic emotion regulatory processes which entailed down-regulation in the amygdala, hippocampus, and temporal pole. Mean scores (±SD) on the Fear of Flying scale dropped from 2.51(±0.65) before the intervention to 1.27(±0.68) after the intervention (p <.001). The proportion of participants meeting the criteria for fear of flying also dropped from 89.7 percent before the intervention to 24.0 percent after the intervention (p <.001). Taken together, our results lend support to the effectiveness of tapping as a means of emotion regulation across multiple contexts and add to previous findings of increased amygdala activation during tapping, as opposed to amygdala down-regulation found in other emotion regulation techniques. They expand on previous knowledge by suggesting that tapping might modulate the processing of complex visual scene representations and their binding with visceral emotional reponses, reflected by the down-regulation of activation in the hippocampus and temporal pole. Bifocal emotion regulation was useful in ameliorating aversive reactions to phobic stimuli in people with fear of flying.