Symposium
Novel circuits for the control of emotion linked with psychiatric disorders
シンポジウム
精神病態解明に向けた情動制御回路研究の新展開 |
|---|
| 7月27日（土）14:21～14:45 第3会場（朱鷺メッセ 2F メインホールB）
3S03a-1
Dissecting Locus Coeruleus Noradrenergic Circuits in Stress and Anxiety
Michael R Bruchas（Bruchas Michael R）1，Andrew Luskin（Luskin Andrew）1，Kelsey Barcomb（Barcomb Kelsey）2，Chris Ford（Ford Chris）2
1University of Washington
2University of Colorado - Denver
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety or regulating stressful contextual information has not been elucidated. We have worked over the last several years to dissect the efferent and afferent circuits that influence LC - NE function and/or the structures where the LC outputs its influence into particular regions (i.e., BLA). Here I will describe recent studies whereby we have been investigating how the LC gates generalizable fear behaviors in mice, as well as how we have recently identified a local peri-LC neuronal population that dramatically regulates anxiety-like behaviors and tonically controls LC-NE function via direct connectivity to LC-NE neurons. I will highlight how we have used a combination of technical approaches, including optogenetics, chemogenetics, pharmacology, fiber photometry and in vivo calcium imaging to understand the LC's function in stress and anxiety-related behavior. In addition, I will discuss how some of our recent work has identified a role for specific downstream GPCR effectors, including beta-adrenergic receptors in LC-related anxiety and stress-regulated behaviors. | | 7月27日（土）14:45～15:08 第3会場（朱鷺メッセ 2F メインホールB）
3S03a-2
恐怖記憶エングラムによる再固定化と消去の制御
Satoshi Kida（喜田 聡）
東京農大バイオ
Memory retrieval is not a passive process. Retrieval of contextual fear memory by short or long reminders initiates reconsolidation and extinction, respectively; reconsolidation maintains or enhances fear memory, while extinction weakens it. We have tried to understand mechanism for regulation of fear memory after retrieval at the molecular, cellular and circuits levels using contextual fear conditioning and inhibitory avoidance tasks. Our previous studies showed that reconsolidation of fear memory requires the activation of gene expression in the hippocampus, mPFC and amygdala, while long-term extinction requires gene expression activation in the mPFC and amygdala. Based on these findings, we are trying to identify and characterize ""fear"" and ""extinction"" engram neurons in the hippocampus, mPFC and amygdala.
We identified fear engram neurons in the hippocampus and examined the function of these neurons using c-fos-tag system. Fear engram neurons were labeled by ChR2 or ArchT and effects of optogenetic activation and inactivation of them were examined during memory retrieval. Inactivation of fear engram neurons during retrieval erased contextual fear memory, perhaps, by blocking memory reconsolidation, whereas activation of these engrams during retrieval blocked acquisition and consolidation of fear memory extinction. These results suggest that modulation of hippocampal fear memory engram cells are crucial processes to determine the fate of memory; reconsolidation or extinction.
We also identified fear and extinction engram neurons in the amygdala and mPFC. Interestingly, distinct fear and extinction engram neurons were observed in the amygdala, while single neuronal fear/extinction engram neurons was observed in the mPFC. We are now characterizing these engram neurons using optogenetics. | | 7月27日（土）15:08～15:32 第3会場（朱鷺メッセ 2F メインホールB）
3S03a-3
Prefrontal cortex and midline thalamic output circuits guide reward seeking through divergent cue encoding
Garret Stuber（Stuber Garret）
University of Washington
The medial prefrontal cortex (PFC) is a critical hub for orchestrating motivated and emotional behaviors across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking, such as the nucleus accumbens (NAc), ventral tegmental area, and midline thalamic areas such as the periventricular thalamus (PVT). While connectivity among these structures contributes to appetitive behaviors, how projection-specific prefrontal neurons encode reward-relevant information to guide aspects of behavior is largely unknown. We used in vivo two-photon calcium imaging in awake and behaving mice to monitor the activity of dorsomedial prefrontal neurons and midline thalamic neurons in mice during a Pavlovian conditioning task. Over multiple conditioning sessions, mice were trained to associated the delivery of sucrose (appetitive) with a neutral auditory tone. Cue-reward learning was indicated by the expression of anticipatory licking to the cue that predicts sucrose while mice generally withheld licking on trials when quinine was delivered. We quantified time-locked changes in calcium activity in multiple classes of PFC output neurons as well as PVT neurons that project to the NAc. At the population level, PFC neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from PFC neurons with resolved projection targets reveal that individual PFC-NAc neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, PFC-PVT neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of PFC-NAc neurons promotes conditioned reward-seeking behavior after learning, while activity in PFC-PVT neurons suppresses both the acquisition and expression of conditioned reward seeking. With respect to PVT neurons, data reveal that while some of these cells have excitatory responses to the cue associated with sucrose after learning, other PVT neurons have inhibitory response profiles. These data show how PFC circuitry as well as neurons in the PVT can dynamically control reward-seeking behavior and decision making. | | 7月27日（土）15:32～15:56 第3会場（朱鷺メッセ 2F メインホールB）
3S03a-4
Neural Circuit Mechanism of Social Hierarchy
Hailan Hu（Hu Hailan）
Zhejiang University
Dominance hierarchy has a great impact on societal function and individuals' life quality. The social economic status has been identified as the single strongest predictor of health. Getting to the top of the social hierarchy is not simply determined by brute strength, but by personality traits such as grit, and social experience such as history of winning or losing. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear.
Working in mice, my lab has previously discovered that the social hierarchical status of the animal correlates with the synaptic strength in the dorsal medial prefrontal cortex (dmPFC) neurons (Science, 2011). Furthermore, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing effort-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. Thus this mPFC-based neural circuitry may underlies the ""winner effect"";, where animals increase their chance of victory after repeated winning (Science, 2017). In the present talk
I will present our latest progress on mapping the mPFC downstream neural circuit involved in social hierarchy regulation. I will also show endoscope calcium imaging data revealing the dynamics of mPFC activity during the formation and reconfiguration of social hierarchy. | | 7月27日（土）15:56～16:20 第3会場（朱鷺メッセ 2F メインホールB）
3S03a-5
Memory codes in the dentate gyrus
Mazen Kheirbek（Kheirbek Mazen）
University of California, San Francisco
A central goal of neuroscience is to understand how sensory stimuli are encoded within ensembles of neurons, and how these representations are modified by learning. The hippocampus (HPC) has a well-documented function in encoding spatial information, however, it also encodes non-spatial information crucial for memory formation. Granule cells (GCs) in the dentate gyrus (DG) have been implicated in memory generalization, a process impaired in individuals with anxiety disorders such as post-traumatic stress. DG GCs receive input from the lateral entorhinal cortex, which is known to process non-spatial olfactory information. Thus, we leveraged the use of odor stimuli to understand general principles of stimulus encoding and memory formation in DG GCs. We used in vivo 2-photon calcium imaging combined with behavior to determine the mechanisms by which DG GCs represent odor information and how fear learning alters these representations. We found that a subset of DG GCs show odor-selectivity, responding to individual or pairs of odors, as well as odor offset. Using machine learning techniques, we were able to predict odor identity from DG GC activity with very high accuracy for three odor cues. Moreover, decoding accuracy was just as high in deciphering similar odors as between distinct odor pairs, supporting the notion that the DG is a structure involved in pattern separation. In learning studies, mice were presented with two similar odorants and one distinct odorant, with one of the similar odorants conditioned with a footshock (CS+). Remarkably, odor classification accuracy before conditioning predicted the animal's behavioral discrimination between similar odor pairs. To determine how neural representations change with learning, we tracked activity in the same neurons before and after conditioning. Fear learning led to an increase in cells that maintained stable tuning to the CS+ odor and the similar odor when compared to mice not exposed to a footshock. These studies demonstrate that odor identity is robustly encoded within the DG, and that fear learning stabilizes these representations providing evidence for olfactory memory traces in the dentate gyrus. | | | |
|
|
