ABSTRACTBACKGROUNDOne major hallmark of alcohol use disorder (AUD) is the persistence of alcohol ... more ABSTRACTBACKGROUNDOne major hallmark of alcohol use disorder (AUD) is the persistence of alcohol drinking despite negative consequences. Among the indicators of AUD vulnerability, binge drinking is a strong risk factor. Although the lifetime prevalence of binge and AUD has been historically higher in men than women, this gap dramatically narrowed in the last decade. Additionally, sex differences in AUD and binge drinking have been shown in clinical and preclinical studies, respectively. The insular cortex plays an important role in AUD, and the anterior (aIC) and posterior (pIC) divisions have dimorphic functions. However, the contributions of the aIC and pIC sections in alcohol binge drinking and alcohol persistent drinking despite aversion, as well as the sexual dimorphism of these contributions, remained to be uncovered.METHODSFirst, by combining the drinking in the dark model with chemogenetics, we studied the causal role of aIC and pIC excitatory neurons in binge and persistent...
Rationale The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have... more Rationale The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. Objectives We seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. Methods Here, we use optogenetics and in vivo electrophysiological recordings to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. Results We find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. Conclusion We conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified.
The ability to associate temporally segregated information and assign positive or negative valenc... more The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different basolateral amygdala (BLA) projections are potentiated following reward or punishment learning 1-7. However, we do not yet understand how valence specific information is routed to the BLA neurons with the appropriate downstream projections. Nor do we understand how to reconcile the subsecond timescales of synaptic plasticity 8-11 with the longer timescales separating the predictive cues from their outcomes. Here, we demonstrate that neurotensin (NT) neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, while PVT-BLA projection-specific Nt gene knockout augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium Li et al.
Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are... more Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.
Intracellular calcium signaling underlies the astroglial control of synaptic transmission and pla... more Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB1) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB1 receptors or dominant-negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions.
Water intake is regulated by neocortical top-down circuits, but their identity and the cellular m... more Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.
The neural mechanisms underlying emotional valence are at the interface between perception and ac... more The neural mechanisms underlying emotional valence are at the interface between perception and action, integrating inputs from the external environment with past experiences to guide the behavior of an organism. Depending on the positive or negative valence assigned to an environmental stimulus, the organism will approach or avoid the source of the stimulus. Multiple convergent studies have demonstrated that the amygdala complex is a critical node of the circuits assigning valence. Here we examine the current progress in identifying valence coding properties of neural populations in different nuclei of the amygdala, based on their activity, connectivity, and gene expression profile. Neural substrate of valence The concept of valence Across the animal kingdom, environmental stimuli can elicit a repertoire of behavioral responses ranging from approach to avoidance. Valence is the subjective value assigned to sensory stimuli which determines subsequent behavior. Positive valence leads to approach and consummatory behaviors while negative valence leads to defensive and avoidance behaviors [1,2]. For many sensory stimuli the assigned valence is innate, however, valence is weighted by the internal state of the organism and by its previous experiences [3,4] (Box 1). A simple example of state-dependence of valence is the value assigned to food, which strongly depends on the homeostatic needs of the animal [5]. Another internal state regulating valence assignment is basal anxiety. Indeed, high anxiety levels can induces a bias towards negative valence, even for stimuli that are normally rewarding [6]. Despite the fundamental role of valence on animal survival and well-being, the underlying neurobiological substrate remains partially understood. One of the main working hypothesis postulates that specific neural circuits assign valence to stimuli in order to activate defined motor patterns and ensure an adaptive behavioral response [3,7]. In line with this hypothesis, human brain imaging has identified divergent networks activated in response to stimuli of
In vitro studies have reported high intracellular chloride levels, depolarizing and potentially e... more In vitro studies have reported high intracellular chloride levels, depolarizing and potentially excitatory actions of GABA in various pathological conditions. Consequently, great expectations are now pinned on drugs potentially restoring low [Cl−]i as novel therapies for a wide range of brain disorders. However, the clinical relevance of this hypothesis remains largely speculative because of the yet unresolved technical difficulty to evaluate the polarity of GABAergic transmission in vivo. Here, we show that the polarity of GABAergic transmission can be probed across the CA3 hippocampal circuit in vivo with single cell resolution, by combining extracellular detection of unitary inhibitory postsynaptic field-potentials (fIPSPs) and silicon probe recording of the firing activity of multiple individually identified neurons. As an example application, we provide direct evidence for depolarizing actions of perisomatic GABAergic transmission and time-locked excitation of CA3 pyramidal neu...
ABSTRACTThe insular cortex, or insula, is a large brain region involved in the detection of thirs... more ABSTRACTThe insular cortex, or insula, is a large brain region involved in the detection of thirst and the control of water intake. However our understanding of the topographical, circuit and molecular mechanisms the controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid receptors (CB1) within the insular cortex participate to the regulation of water intake, and deconstructed circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both anterior (aIC) and posterior (pIC) insula increases in response to water intake, yet removal of CB1 receptors only in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we imaged the neurons of the anterior or posterior insula targeting the BLA (aIC-BLA and pIC-BLA), and found they oppo...
Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are ... more Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxietylike behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).
SummaryIn the quest for food, we may expend effort and increase our vulnerability to potential th... more SummaryIn the quest for food, we may expend effort and increase our vulnerability to potential threats. Motivation to seek food is dynamic, varying with homeostatic need. What mechanisms underlie these changes? Basolateral amygdala neurons projecting to the nucleus accumbens (BLA→NAc) preferentially encode positive valence, whereas those targeting the centromedial amygdala (BLA→CeM) preferentially encode negative valence. Longitudinal in vivo two-photon calcium imaging revealed that BLA→NAc neurons were more active, while BLA→CeM neurons were less active, following just 1 day of food deprivation. Photostimulating BLA→CeM neurons inhibited BLA→NAc neurons at baseline, but food deprivation rapidly converted this inhibition into facilitation, supporting a model wherein BLA→NAc excitability mediates invigorated food-seeking behavior after deprivation. Indeed, inhibiting BLA→NAc reduced motivation for a caloric reinforcer in food deprived animals. Taken together, negative valence overrid...
ChR2 eYFP mPFC L2/3 L1 L5 L6 d l TH VTA DA ::mCherry LC NA ::eYFP DAPI OFF ON Time in port during... more ChR2 eYFP mPFC L2/3 L1 L5 L6 d l TH VTA DA ::mCherry LC NA ::eYFP DAPI OFF ON Time in port during CS comp (%) Time freezing during CS comp (%) a c d Time (s) 30 0 Time in port (%) 100 0 80 Time freezing (%) h Time (s) 30 0 Cue C ue FSCV VTA mPFC Sucrose ON OFF CS suc + CS shk 0 20 Time (s) Vacuum Shock g
The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulati... more The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits und...
Observational learning is a powerful survival tool allowing individuals to learn about threat-pre... more Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this...
Orchestrating appropriate behavioral responses in the face of competing signals that predict eith... more Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fearrelated responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock-and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
ABSTRACTBACKGROUNDOne major hallmark of alcohol use disorder (AUD) is the persistence of alcohol ... more ABSTRACTBACKGROUNDOne major hallmark of alcohol use disorder (AUD) is the persistence of alcohol drinking despite negative consequences. Among the indicators of AUD vulnerability, binge drinking is a strong risk factor. Although the lifetime prevalence of binge and AUD has been historically higher in men than women, this gap dramatically narrowed in the last decade. Additionally, sex differences in AUD and binge drinking have been shown in clinical and preclinical studies, respectively. The insular cortex plays an important role in AUD, and the anterior (aIC) and posterior (pIC) divisions have dimorphic functions. However, the contributions of the aIC and pIC sections in alcohol binge drinking and alcohol persistent drinking despite aversion, as well as the sexual dimorphism of these contributions, remained to be uncovered.METHODSFirst, by combining the drinking in the dark model with chemogenetics, we studied the causal role of aIC and pIC excitatory neurons in binge and persistent...
Rationale The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have... more Rationale The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. Objectives We seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. Methods Here, we use optogenetics and in vivo electrophysiological recordings to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. Results We find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. Conclusion We conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified.
The ability to associate temporally segregated information and assign positive or negative valenc... more The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different basolateral amygdala (BLA) projections are potentiated following reward or punishment learning 1-7. However, we do not yet understand how valence specific information is routed to the BLA neurons with the appropriate downstream projections. Nor do we understand how to reconcile the subsecond timescales of synaptic plasticity 8-11 with the longer timescales separating the predictive cues from their outcomes. Here, we demonstrate that neurotensin (NT) neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, while PVT-BLA projection-specific Nt gene knockout augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium Li et al.
Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are... more Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.
Intracellular calcium signaling underlies the astroglial control of synaptic transmission and pla... more Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB1) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB1 receptors or dominant-negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions.
Water intake is regulated by neocortical top-down circuits, but their identity and the cellular m... more Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.
The neural mechanisms underlying emotional valence are at the interface between perception and ac... more The neural mechanisms underlying emotional valence are at the interface between perception and action, integrating inputs from the external environment with past experiences to guide the behavior of an organism. Depending on the positive or negative valence assigned to an environmental stimulus, the organism will approach or avoid the source of the stimulus. Multiple convergent studies have demonstrated that the amygdala complex is a critical node of the circuits assigning valence. Here we examine the current progress in identifying valence coding properties of neural populations in different nuclei of the amygdala, based on their activity, connectivity, and gene expression profile. Neural substrate of valence The concept of valence Across the animal kingdom, environmental stimuli can elicit a repertoire of behavioral responses ranging from approach to avoidance. Valence is the subjective value assigned to sensory stimuli which determines subsequent behavior. Positive valence leads to approach and consummatory behaviors while negative valence leads to defensive and avoidance behaviors [1,2]. For many sensory stimuli the assigned valence is innate, however, valence is weighted by the internal state of the organism and by its previous experiences [3,4] (Box 1). A simple example of state-dependence of valence is the value assigned to food, which strongly depends on the homeostatic needs of the animal [5]. Another internal state regulating valence assignment is basal anxiety. Indeed, high anxiety levels can induces a bias towards negative valence, even for stimuli that are normally rewarding [6]. Despite the fundamental role of valence on animal survival and well-being, the underlying neurobiological substrate remains partially understood. One of the main working hypothesis postulates that specific neural circuits assign valence to stimuli in order to activate defined motor patterns and ensure an adaptive behavioral response [3,7]. In line with this hypothesis, human brain imaging has identified divergent networks activated in response to stimuli of
In vitro studies have reported high intracellular chloride levels, depolarizing and potentially e... more In vitro studies have reported high intracellular chloride levels, depolarizing and potentially excitatory actions of GABA in various pathological conditions. Consequently, great expectations are now pinned on drugs potentially restoring low [Cl−]i as novel therapies for a wide range of brain disorders. However, the clinical relevance of this hypothesis remains largely speculative because of the yet unresolved technical difficulty to evaluate the polarity of GABAergic transmission in vivo. Here, we show that the polarity of GABAergic transmission can be probed across the CA3 hippocampal circuit in vivo with single cell resolution, by combining extracellular detection of unitary inhibitory postsynaptic field-potentials (fIPSPs) and silicon probe recording of the firing activity of multiple individually identified neurons. As an example application, we provide direct evidence for depolarizing actions of perisomatic GABAergic transmission and time-locked excitation of CA3 pyramidal neu...
ABSTRACTThe insular cortex, or insula, is a large brain region involved in the detection of thirs... more ABSTRACTThe insular cortex, or insula, is a large brain region involved in the detection of thirst and the control of water intake. However our understanding of the topographical, circuit and molecular mechanisms the controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid receptors (CB1) within the insular cortex participate to the regulation of water intake, and deconstructed circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both anterior (aIC) and posterior (pIC) insula increases in response to water intake, yet removal of CB1 receptors only in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we imaged the neurons of the anterior or posterior insula targeting the BLA (aIC-BLA and pIC-BLA), and found they oppo...
Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are ... more Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxietylike behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).
SummaryIn the quest for food, we may expend effort and increase our vulnerability to potential th... more SummaryIn the quest for food, we may expend effort and increase our vulnerability to potential threats. Motivation to seek food is dynamic, varying with homeostatic need. What mechanisms underlie these changes? Basolateral amygdala neurons projecting to the nucleus accumbens (BLA→NAc) preferentially encode positive valence, whereas those targeting the centromedial amygdala (BLA→CeM) preferentially encode negative valence. Longitudinal in vivo two-photon calcium imaging revealed that BLA→NAc neurons were more active, while BLA→CeM neurons were less active, following just 1 day of food deprivation. Photostimulating BLA→CeM neurons inhibited BLA→NAc neurons at baseline, but food deprivation rapidly converted this inhibition into facilitation, supporting a model wherein BLA→NAc excitability mediates invigorated food-seeking behavior after deprivation. Indeed, inhibiting BLA→NAc reduced motivation for a caloric reinforcer in food deprived animals. Taken together, negative valence overrid...
ChR2 eYFP mPFC L2/3 L1 L5 L6 d l TH VTA DA ::mCherry LC NA ::eYFP DAPI OFF ON Time in port during... more ChR2 eYFP mPFC L2/3 L1 L5 L6 d l TH VTA DA ::mCherry LC NA ::eYFP DAPI OFF ON Time in port during CS comp (%) Time freezing during CS comp (%) a c d Time (s) 30 0 Time in port (%) 100 0 80 Time freezing (%) h Time (s) 30 0 Cue C ue FSCV VTA mPFC Sucrose ON OFF CS suc + CS shk 0 20 Time (s) Vacuum Shock g
The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulati... more The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits und...
Observational learning is a powerful survival tool allowing individuals to learn about threat-pre... more Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this...
Orchestrating appropriate behavioral responses in the face of competing signals that predict eith... more Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fearrelated responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock-and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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Papers by Anna Beyeler
Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.
Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders.