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24/01/2018 | Neuron   IF 14.3
Prefrontal-Periaqueductal Gray-Projecting Neurons Mediate Context Fear Discrimination.
Rozeske RR, Jercog D, Karalis N, Chaudun F, Khoder S, Girard D, Winke N, Herry C

Survival critically depends on selecting appropriate defensive or exploratory behaviors and is strongly influenced by the surrounding environment. Contextual discrimination is a fundamental process that is thought to depend on the prefrontal cortex to integrate sensory information from the environment and regulate adaptive responses to threat during uncertainty. However, the precise prefrontal circuits necessary for discriminating a previously threatening context from a neutral context remain unknown. Using a combination of single-unit recordings and optogenetic manipulations, we identified a neuronal subpopulation in the dorsal medial prefrontal cortex (dmPFC) that projects to the lateral and ventrolateral periaqueductal gray (l/vlPAG) and is selectively activated during contextual fear discrimination. Moreover, optogenetic activation and inhibition of this neuronal population promoted contextual fear discrimination and generalization, respectively. Our results identify a subpopulation of dmPFC-l/vlPAG-projecting neurons that control switching between different emotional states during contextual discrimination.

15/02/2016 | Nat Neurosci   IF 19.9
4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.
Karalis N, Dejean C, Chaudun F, Khoder S, Rozeske RR, Wurtz H, Bagur S, Benchenane K, Sirota A, Courtin J, Herry C

Fear expression relies on the coordinated activity of prefrontal and amygdala circuits, yet the mechanisms allowing long-range network synchronization during fear remain unknown. Using a combination of extracellular recordings, pharmacological and optogenetic manipulations, we found that freezing, a behavioral expression of fear, temporally coincided with the development of sustained, internally generated 4-Hz oscillations in prefrontal-amygdala circuits. 4-Hz oscillations predict freezing onset and offset and synchronize prefrontal-amygdala circuits. Optogenetic induction of prefrontal 4-Hz oscillations coordinates prefrontal-amygdala activity and elicits fear behavior. These results unravel a sustained oscillatory mechanism mediating prefrontal-amygdala coupling during fear behavior.

01/09/2015 | Biol Psychiatry   IF 12
Neuronal Circuits for Fear Expression and Recovery: Recent Advances and Potential Therapeutic Strategies.
Dejean C, Courtin J, Rozeske RR, Bonnet MC, Dousset V, Michelet T, Herry C

Recent technological developments, such as single unit recordings coupled to optogenetic approaches, have provided unprecedented knowledge about the precise neuronal circuits contributing to the expression and recovery of conditioned fear behavior. These data have provided an understanding of the contributions of distinct brain regions such as the amygdala, prefrontal cortex, hippocampus, and periaqueductal gray matter to the control of conditioned fear behavior. Notably, the precise manipulation and identification of specific cell types by optogenetic techniques have provided novel avenues to establish causal links between changes in neuronal activity that develop in dedicated neuronal structures and the short and long-lasting expression of conditioned fear memories. In this review, we provide an update on the key neuronal circuits and cell types mediating conditioned fear expression and recovery and how these new discoveries might refine therapeutic approaches for psychiatric conditions such as anxiety disorders and posttraumatic stress disorder.

07/10/2014 | Genes Brain Behav   IF 3.5
Prefrontal neuronal circuits of contextual fear conditioning.
Rozeske RR, Valerio S, Chaudun F, Herry C

Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories.

02/01/2014 | Nature   IF 41.6
Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.
Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, Abdi A, Baufreton J, Bienvenu TC, Herry C

Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (gamma-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

2013 | Front Behav Neurosci   IF 3.1
Understanding stress resilience.
Baratta MV, Rozeske RR, Maier SF


15/08/2012 | J Neurosci   IF 6
Opioid activation of toll-like receptor 4 contributes to drug reinforcement.
Hutchinson MR, Northcutt AL, Hiranita T, Wang X, Lewis SS, Thomas J, van Steeg K, Kopajtic TA, Loram LC, Sfregola C, Galer E, Miles NE, Bland ST, Amat J, Rozeske RR, Maslanik T, Chapman TR, Strand KA, Fleshner M, Bachtell RK, Somogyi AA, Yin H, Katz JL, Rice KC, Maier SF, Watkins LR

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.

Stress can be a predisposing factor in the development of psychiatric disorders. However, not all individuals develop psychiatric disorders following a traumatic event. An attempt to understand these individual differences has led to a focus on factors that produce resistance. Interestingly, in rats, an experience with escapable tailshock (ES) before inescapable tailshock (IS) prevents the typical anxiety-like behavioral outcomes of IS. This type of resistance has been termed 'behavioral immunization', and it depends on activation of the medial prefrontal cortex (mPFC) during ES. However, one outcome of IS that is not anxiety-related is potentiation of morphine conditioned place preference (CPP). The present experiments investigated whether prior ES would block IS-induced potentiation of morphine CPP. Rats received either ES, IS or homecage control treatment on day 1 and then either IS or homecage control treatment on day 2. Twenty-four hours following day 2, rats underwent morphine conditioning, and CPP was subsequently assessed. In a second experiment, rats received ES 3, 14 or 56 days prior to IS to determine the duration of behavioral immunization. In a final experiment, rats were microinjected with the GABA(A) agonist muscimol (50 ng/0.5 muL) or saline in the mPFC before day 1 of stress. Prior ES blocked IS-induced potentiation of morphine CPP. This immunizing effect of ES lasted for at least 56 days. Additionally, intra-mPFC muscimol during ES prevented behavioral immunization. These results suggest that prior experience with ES activates the mPFC and produces long-lasting neural alterations that block subsequent IS-induced potentiation of morphine CPP.

05/10/2011 | J Neurosci   IF 6
Uncontrollable, but not controllable, stress desensitizes 5-HT1A receptors in the dorsal raphe nucleus.
Rozeske RR, Evans AK, Frank MG, Watkins LR, Lowry CA, Maier SF

Uncontrollable stressors produce behavioral changes that do not occur if the organism can exercise behavioral control over the stressor. Previous studies suggest that the behavioral consequences of uncontrollable stress depend on hypersensitivity of serotonergic neurons in the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used ex vivo single-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT(1A) autoreceptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT(1A) receptor-mediated inhibition of DRN neuronal firing. Moreover, this effect was observed only at time points when the behavioral effects of uncontrollable stress are present. Furthermore, temporary inactivation of the medial prefrontal cortex with the GABA(A) receptor agonist muscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT(1A) receptors. Additionally, behavioral immunization, an experience with controllable stress before uncontrollable stress that prevents the behavioral outcomes of uncontrollable stress, also blocked functional desensitization of DRN 5-HT(1A) receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than downregulation of DRN 5-HT(1A) receptors. Thus, treatments that prevent controllable stress from being protective led to desensitization of 5-HT(1A) receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT(1A) receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT(1A) autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress.

01/06/2011 | Behav Brain Res   IF 3.2
Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference.
Rozeske RR, Greenwood BN, Fleshner M, Watkins LR, Maier SF

In rodents, exposure to acute inescapable, but not escapable, stress potentiates morphine conditioned place preference (CPP), an effect that is dependent upon hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Six weeks of voluntary wheel running constrains activation of DRN 5-HT neurons during exposure to inescapable stress. Six weeks of voluntary wheel running before inescapable stress blocked stress-induced potentiation of morphine CPP.