Periaqueductal gray activates antipredatory neural responses in the amygdala of foraging rats.

Pavlovian fear conditioning research suggests that the interaction between the dorsal periaqueductal gray (dPAG) and basolateral amygdala (BLA) acts as a prediction error mechanism in the formation of associative fear memories. However, their roles in responding to naturalistic predatory threats, characterized by less explicit cues and the absence of reiterative trial-and-error learning events, remain unexplored. In this study, we conducted single-unit recordings in rats during an 'approach food-avoid predator' task, focusing on the responsiveness of dPAG and BLA neurons to a rapidly approaching robot predator. Optogenetic stimulation of the dPAG triggered fleeing behaviors and increased BLA activity in naive rats. Notably, BLA neurons activated by dPAG stimulation displayed immediate responses to the robot, demonstrating heightened synchronous activity compared to BLA neurons that did not respond to dPAG stimulation. Additionally, the use of anterograde and retrograde tracer injections into the dPAG and BLA, respectively, coupled with c-Fos activation in response to predatory threats, indicates that the midline thalamus may play an intermediary role in innate antipredatory defensive functioning.

The anterior insular cortex processes social recognition memory.

Impaired social abilities are characteristics of a variety of psychiatric disorders such as schizophrenia, autism spectrum disorder, and bipolar disorder. Studies consistently implicated the relationship between the anterior insular cortex (aIC) and social ability, however, how the aIC involves in processing specific subtypes of social ability was uninvestigated. We, therefore, investigated whether the absence or presence of the aIC affects the social behaviors of mice. We found that electrolytic lesions of the aIC specifically impaired mice's ability to recognize a novel stranger mouse, while the sociability of the aIC-lesioned mice was intact. Interestingly, the aIC-lesioned mice were still distinguished between a mouse that had been housed together before the aIC lesion and a novel mouse, supporting that retrieval of social recognition memory may not involve the aIC. Additional behavioral tests revealed that this specific social ability impairment induced by the aIC lesion was not due to impairment in olfaction, learning and memory, locomotion, or anxiety levels. Together our data suggest that the aIC is specifically involved in processing social recognition memory, but not necessarily involved in retrieving it.

Cage-Embedded Crown-Type Dual Coil Wireless Power Transfer Based Microwave Brain Stimulation System for Untethered and Moving Mice.

This study proposes a novel brain-stimulated mouse experiment system which is insensitive to the variations in the position and orientation of a mouse. This is achieved by the proposed novel crown-type dual coil system for magnetically coupled resonant wireless power transfer (MCR-WPT). In the detailed system architecture, the transmitter coil consists of a crown-type outer coil and a solenoid-type inner coil. The crown-type coil was constructed by repeating the rising and falling at an angle of 15 ° for each side which creates the H-field diverse direction. The solenoid-type inner coil creates a magnetic field distributed uniformly along the location. Therefore, despite using two coils for the Tx system, the system generates the H-field insensitive to the variations in the position and angle of the receiver system. The receiver is comprised of the receiving coil, rectifier, divider, LED indicator, and the MMIC that generates the microwave signal for stimulating the brain of the mouse. The system resonating at 2.84 MHz was simplified to easy fabrication by constructing 2 transmitter coils and 1 receiver coil. A peak PTE of 19.6% and a PDL of 1.93 W were achieved, and the system also achieved an operation time ratio of 89.55% in vivo experiments. As a result, it is confirmed that experiments could proceed for approximately 7 times longer through the proposed system compared to the conventional dual coil system.

Lateral habenula lesions impair the association of a conditioned stimulus with the absence of an unconditioned stimulus: Retardation task.

Recent studies have indicated that the lateral habenula (LHb) mediates the association of a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US). We generated a CS-no US association using an explicit unpaired training procedure and evaluated the conditioned inhibitory properties using the modified version of the retardation-of-acquisition procedure, one of the procedures for assessing conditioned inhibition. First, rats in the unpaired group received explicit unpaired light (CS) and food (US) presentations, followed by light-food pairings. Rats in the comparison group received paired training alone. The rats in the two groups showed increased food-cup responses to light over paired training. However, rats in the unpaired group showed a slower acquisition of light and food excitatory conditioning than those in the comparison group. Light acquired conditioned inhibitory properties through explicitly unpaired training, as evidenced by its slowness. Second, we examined the effects of the LHb lesions on the decremental effects of unpaired learning on subsequent excitatory learning. Sham-operated rats exhibited decremental effects of unpaired learning on subsequent excitatory learning, while rats with LHb neurotoxic lesions did not. Third, we tested whether preexposure to the same number of lights presented in the unpaired training retarded the acquisition of subsequent excitatory conditioning. Preexposure to light did not significantly retard the acquisition of subsequent excitatory associations, with no LHb lesion effects. These findings indicate that LHb is critically involved in the association between CS and the absence of US.

Distinct Role of Parvalbumin Expressing Neurons in the Reticular Thalamic Nucleus in Nociception.

Loss of inhibition is suggested to cause pathological pain symptoms. Indeed, some human case reports suggest that lesions including the thalamic reticular nucleus (TRN) which provides major inhibitory inputs to other thalamic nuclei, may induce thalamic pain, a type of neuropathic pain. In support, recent studies demonstrated that activation of GABAergic neurons in the TRN reduces nociceptive responses in mice, reiterating the importance of the TRN in gating nociception. However, whether biochemically distinct neuronal types in the TRN differentially contribute to gating nociception has not been investigated. We, therefore, investigated whether the activity of parvalbumin (PV) and somatostatin (SOM) expressing neurons in the somatosensory TRN differentially modulate nociceptive behaviors using optogenetics and immunostaining techniques. We found that activation of PV neurons in the somatosensory TRN significantly reduced nociceptive behaviors, while activation of SOM neurons in the TRN had no such effect. Also, selective activation of PV neurons, but not SOM neurons, in the TRN activated relatively more PV neurons in the primary somatosensory cortex, which delivers inhibitory effect in the cortex, when measured with cFos and PV double staining. Results of our study suggest that PV neurons in the somatosensory TRN have a stronger influence in regulating nociception and that their activations may provide further inhibition in the somatosensory cortex by activating cortical PV neurons.

Role of the anterior insular cortex in restraint-stress induced fear behaviors.

Anxiety disorders, such as post-traumatic stress disorder (PTSD), are thought to occur by dysfunction in the fear and anxiety-related brain circuit, however, the exact mechanisms remain unknown. Recent human studies have shown that the right anterior insular cortex (aIC) activity is positively correlated with the severity of PTSD symptoms. Understanding the role of the aIC in fear and anxiety may provide insights into the etiology of anxiety disorders. We used a modified shock-probe defensive burying behavioral test, which utilizes the natural propensity of rodents to bury potentially dangerous objects, to test the role of aIC in fear. Mice exposed to restraint stress exhibited burying of the restrainer-resembling object, indicative of defensive behavior. Electrolytic ablation of the aIC significantly diminished this defensive burying behavior, suggesting the involvement of the aIC. Single-unit recording of pyramidal neurons in the aIC showed that a proportion of neurons which increased activity in the presence of a restrainer-resembling object was significantly correlated with the defensive burying behavior. This correlation was only present in mice exposed to restraint stress. These results suggest that altered neuronal representation in the aIC may regulate fear and anxiety after exposure to a traumatic event. Overall, our result demonstrates that the aIC mediates fear and anxiety and that it could be a potential target for treating anxiety disorders.

Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus.

BACKGROUND: NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility. METHODS: We employed cell type-specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. RESULTS: We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and α1 adrenergic receptor-dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning. CONCLUSIONS: These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.

'Fearful-place' coding in the amygdala-hippocampal network.

Animals seeking survival needs must be able to assess different locations of threats in their habitat. However, the neural integration of spatial and risk information essential for guiding goal-directed behavior remains poorly understood. Thus, we investigated simultaneous activities of fear-responsive basal amygdala (BA) and place-responsive dorsal hippocampus (dHPC) neurons as rats left the safe nest to search for food in an exposed space and encountered a simulated 'predator.' In this realistic situation, BA cells increased their firing rates and dHPC place cells decreased their spatial stability near the threat. Importantly, only those dHPC cells synchronized with the predator-responsive BA cells remapped significantly as a function of escalating risk location. Moreover, optogenetic stimulation of BA neurons was sufficient to cause spatial avoidance behavior and disrupt place fields. These results suggest a dynamic interaction of BA's fear signalling cells and dHPC's spatial coding cells as animals traverse safe-danger areas of their environment.

SGK1 knockdown in the medial prefrontal cortex reduces resistance to stress-induced memory impairment.

Down-regulation of serum and glucocorticoid-regulated kinase1 (SGK1) expression has been reported in the postmortem prefrontal cortex (PFC) of subjects with post-traumatic stress disorder. Furthermore, experimental treatments that reduce SGK1 function in the medial prefrontal cortex (mPFC) cause depressive-like behaviors and synaptic dysfunction. Therefore, we examined the effect of SGK1 down-regulation in the mPFC on resistance to stress-induced cognitive impairment. Rats with viral-mediated knockdown of SGK1 in the mPFC were subjected to either a brief 20-min restraint plus 20 intermittent tail shocks or a prolonged 60-min restraint plus 60 intermittent tail shocks, after which their performance in an object recognition task was assessed. Recognition memory remained intact in control rats following the brief stress, but was impaired in rats with SGK1 knockdown in the mPFC. Prolonged stress impaired recognition memory in both control rats and rats with SGK1 knockdown. Our findings indicate that altered mPFC SGK1 signaling is a potential mechanism for resistance to stress-induced cognitive impairment.

Astrocytic Calcium Dynamics Along the Pain Pathway.

Astrocytes, once thought to be passive cells merely filling the space between neurons in the nervous system, are receiving attention as active modulators of the brain and spinal cord physiology by providing nutrients, maintaining homeostasis, and modulating synaptic transmission. Accumulating evidence indicates that astrocytes are critically involved in chronic pain regulation. Injury induces astrocytes to become reactive, and recent studies suggest that reactive astrocytes can have either neuroprotective or neurodegenerative effects. While the exact mechanisms underlying the transition from resting astrocytes to reactive astrocytes remain unknown, astrocytic calcium increase, coordinated by inflammatory molecules, has been suggested to trigger this transition. In this mini review article, we will discuss the roles of astrocytic calcium, channels contributing to calcium dynamics in astrocytes, astrocyte activations along the pain pathway, and possible relationships between astrocytic calcium dynamics and chronic pain.

Brief stress impairs recognition memory through amygdalar activation in animals with medial prefrontal cortex lesions.

The medial prefrontal cortex (mPFC) is thought to exert inhibitory control over stress-induced activation of the amygdala and neurocognitive effects. As evidence to support this, we examined how exposure to either a brief or prolonged stress affected on amygdalar c-Fos levels and recognition memory of animals with mPFC chemical lesions. mPFC-lesioned and sham-operated animals were subjected to either a brief 20-min restraint+20 tailshocks or a prolonged 60-min restraint+60 tailshocks. Post-stress performances in the object recognition memory and c-Fos immunoreactivity in the amygdala were then assessed. In sham-operated animals, the object recognition memory was reliably impaired following the prolonged, but not following the brief stress exposure. On the other hand, in mPFC-lesioned animals, the brief stress significantly impaired recognition memory and enhanced c-Fos expression in the amygdala. Present findings of loss of mPFC activity exacerbating stress effects provide causal evidence that the mPFC exerts inhibitory control on stress.

Autophagy Modulators and Neuroinflammation.

BACKGROUND: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. OBJECTIVE: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. METHODS: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. RESULTS: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. CONCLUSION: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

A Computational Modeling Reveals That Strength of Inhibitory Input, E/I Balance, and Distance of Excitatory Input Modulate Thalamocortical Bursting Properties.

The thalamus is a brain structure known to modulate sensory information before relaying to the cortex. The unique ability of a thalamocortical (TC) neuron to switch between the high frequency burst firing and single spike tonic firing has been implicated to have a key role in sensory modulation including pain. Of the two firing modes, burst firing, especially maintaining certain burst firing properties, was suggested to be critical in controlling nociceptive behaviors. Therefore, understanding the factors that influence burst firing properties would offer important insight into understanding sensory modulation. Using computational modeling, we investigated how the balance of excitatory and inhibitory inputs into a TC neuron influence TC bursting properties. We found that intensity of inhibitory inputs and the timing of excitatory input delivery control the dynamics of bursting properties. Then, to reflect a more realistic model, excitatory inputs delivered at different dendritic locations-proximal, intermediate, or distal-of a TC neuron were also investigated. Interestingly, excitatory input delivered into a distal dendrite, despite the furthest distance, had the strongest influence in shaping burst firing properties, suggesting that not all inputs equally contribute to modulating TC bursting properties. Overall, the results provide computational insights in understanding the detailed mechanism of the factors influencing temporal pattern of thalamic bursts.

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease.

Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

Superior Place Learning of C57BL/6 vs. DBA/2 Mice Following Prior Cued Learning in the Water Maze Depends on Prefrontal Cortical Subregions.

The participation of the prefrontal cortex (PFC), hippocampus, and dorsal striatum in switching the learning task from cued to place learning were examined in C57BL/6 and DBA/2 mice, by assessing changed levels of phosphorylated CREB (pCREB). Mice of both strains first received cued training in a water maze for 4 days (4 trials per day), and were then assigned to one of four groups, one with no place training, and three with different durations of place training (2, 4, or 8 days). Both strains showed equal performance in cued training. After the switch to place training, C57BL/6 mice with 2 or 4 days of training performed significantly better than DBA/2 mice, but their superiority disappeared during the second half of an 8 days-place training period. The pCREB levels of these mice were measured 30 min after place training and compared with those of mice that received only cued training. Changes in pCREB levels of C57BL/6 mice were greater in the hippocampal CA3, hippocampal dentate gyrus, orbitofrontal and medial PFC than those of DBA/2 mice, when mice of both received the switched place training for 2 days. We further investigated the roles of orbitofrontal and medial PFC among these brain regions showing strain differences, by destroying each region using selective neurotoxins. C57BL/6 mice with orbitofrontal lesions were slower to acquire the place learning and continued to use the cued search acquired during the cued training phase. These findings indicate that mouse orbitofrontal cortex (OFC) pCREB is associated with behavioral flexibility such as the ability to switch a learning task.

The Ventral Midline Thalamus Mediates Hippocampal Spatial Information Processes upon Spatial Cue Changes.

The ventral midline thalamus, consisting of the reuniens and rhomboid nuclei (RE/Rh), is a thalamic structure interconnected with the limbic systems including the hippocampus. Recently, many studies have revealed that this structure plays distinctive roles in spatial learning and memory in collaboration with hippocampal functions. However, what aspects of spatial information process are influenced by the RE/Rh is not clearly known. To elucidate the roles of RE/Rh in spatial information processing and its effects on hippocampal activity, specifically with the manipulation of spatial contents, we measured hippocampal-dependent spatial memory performance and hippocampal place cell activities after RE/Rh lesion using male C57BL/6J × 129/SvJae hybrid mice. We found that the lesion altered the behavioral aptitude in recognizing locational changes of an object. Furthermore, CA1 place cells in the lesion group showed different spatial representation patterns in recognizing the environment with cue locational changes compared with the control group. Interestingly, the patterns of CA1 place cells in recognizing the same environment previously visited were not disrupted in the lesion group compared with the control group. These findings demonstrate that the ventral midline thalamus (RE/Rh) is important in recognizing the spatial relationships, especially when spatial rearrangement of cue position was introduced.SIGNIFICANCE STATEMENT The ventral midline thalamic nuclei (reuniens and rhomboid) interact with the hippocampus to influence various cognitive functions requiring spatial memories, yet what aspects of spatial information process are influenced by these nuclei is not clearly known. Here, we reveal that these nuclei play a crucial role in modulating hippocampal properties only with locational rearrangement of cues, not with the familiar arrangement. These nuclei are distinctively involved in cue-dependent spatial information processes of CA1 place cells. In particular, we suggest that these nuclei modulate spatial information processing on discrete components, especially when the spatial cue relationship is modified.

Brain stimulation patterns emulating endogenous thalamocortical input to parvalbumin-expressing interneurons reduce nociception in mice.

BACKGROUND: The bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated. OBJECTIVE: We investigated the role of cortical parvalbumin expressing (PV) interneurons within the TC circuit in gating nociception and their selective response to TC burst patterns. We then tested if transcranial magnetic stimulation (TMS) patterned on endogenous nociceptive TC bursting modulate nociceptive behaviors. METHODS: The switching of TC neurons between tonic (single spike) and burst (high frequency spikes) firing modes may be a critical component in modulating nociceptive signals. Deep brain electrical stimulation of TC neurons and immunohistochemistry were used to examine the differential influence of each firing mode on cortical PV interneuron activity. Optogenetic stimulation of cortical PV interneurons assessed a direct role in nociceptive modulation. A new TMS protocol mimicking thalamic burst firing patterns, contrasted with conventional continuous and intermittent theta burst protocols, tested if TMS patterned on endogenous TC activity reduces nociceptive behaviors in mice. RESULTS: Immunohistochemical evidence confirmed that burst, but not tonic, deep brain stimulation of TC neurons increased the activity of PV interneurons in the cortex. Both optogenetic activation of PV interneurons and TMS protocol mimicking thalamic burst reduced nociceptive behaviors. CONCLUSIONS: Our findings suggest that burst firing of TC neurons recruits PV interneurons in the cortex to reduce nociceptive behaviors and that neuromodulation mimicking thalamic burst firing may be useful for modulating nociception.

Dynamic coding of predatory information between the prelimbic cortex and lateral amygdala in foraging rats.

Predation is considered a major selective pressure in the evolution of fear, but the neurophysiology of predator-induced fear is unknown. We simultaneously recorded lateral amygdala (LA) and prelimbic (PL) area neuronal activities as rats exited a safe nest to search for food in an open space before, during, and after encountering a "predator" robot programmed to surge from afar. Distinct populations of LA neurons transiently increased spiking as rats either advanced or fled the robot, whereas PL neurons showed longer-lasting spike trains that preceded and persisted beyond LA activity. Moreover, discrete LA-PL cell pairs displayed correlated firings only when the animals either approached or fled the robot. These results suggest a general fear function of the LA-PL circuit where the PL participates in the initial detection of potential threats, the LA signals the occurrence of real threats, and the dynamic LA-PL interaction optimizes defensive readiness for action.

Corrigendum: Conditional Knockout of Cav2.1 Disrupts the Accuracy of Spatial Recognition of CA1 Place Cells and Spatial/Contextual Recognition Behavior.

[This corrects the article on p. 214 in vol. 10, PMID: 27857685.].

Differential Responses of Thalamic Reticular Neurons to Nociception in Freely Behaving Mice.

Pain serves an important protective role. However, it can also have debilitating adverse effects if dysfunctional, such as in pathological pain conditions. As part of the thalamocortical circuit, the thalamic reticular nucleus (TRN) has been implicated to have important roles in controlling nociceptive signal transmission. However studies on how TRN neurons, especially how TRN neuronal subtypes categorized by temporal bursting firing patterns-typical bursting, atypical bursting and non-bursting TRN neurons-contribute to nociceptive signal modulation is not known. To reveal the relationship between TRN neuronal subtypes and modulation of nociception, we simultaneously recorded behavioral responses and TRN neuronal activity to formalin induced nociception in freely moving mice. We found that typical bursting TRN neurons had the most robust response to nociception; changes in tonic firing rate of typical TRN neurons exactly matched changes in behavioral nociceptive responses, and burst firing rate of these neurons increased significantly when behavioral nociceptive responses were reduced. This implies that typical TRN neurons could critically modulate ascending nociceptive signals. The role of other TRN neuronal subtypes was less clear; atypical bursting TRN neurons decreased tonic firing rate after the second peak of behavioral nociception and the firing rate of non-bursting TRN neurons mostly remained at baseline level. Overall, our results suggest that different TRN neuronal subtypes contribute differentially to processing formalin induced sustained nociception in freely moving mice.