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Individuals with Parkinson's disease (PD) commonly experience freezing of gait under time constraints, in narrow spaces, and in the dark. One commonality between these different situations is that they may all provoke anxiety, yet anxiety has never been directly examined as a cause of FOG. In this study, virtual reality was used to induce anxiety and evaluate whether it directly causes FOG. Fourteen patients with PD and freezing of gait (Freezers) and 17 PD without freezing of gait (Non-Freezers) were instructed to walk in two virtual environments: (i) across a plank that was located on the ground (LOW), (ii) across a plank above a deep pit (HIGH). Multiple synchronized motion capture cameras updated participants' movement through the virtual environment in real-time, while their gait was recorded. Anxiety levels were evaluated after each trial using self-assessment manikins. Freezers performed the experiment on two separate occasions (in their ON and OFF state). Freezers reported higher levels of anxiety compared to Non-Freezers (p < 0.001) and all patients reported greater levels of anxiety when walking across the HIGH plank compared to the LOW (p < 0.001). Freezers experienced significantly more freezing of gait episodes (p = 0.013) and spent a significantly greater percentage of each trial frozen (p = 0.005) when crossing the HIGH plank. This finding was even more pronounced when comparing Freezers in their OFF state. Freezers also had greater step length variability in the HIGH compared to the LOW condition, while the step length variability in Non-Freezers did not change. In conclusion, this was the first study to directly compare freezing of gait in anxious and non-anxious situations. These results present strong evidence that anxiety is an important mechanism underlying freezing of gait and supports the notion that the limbic system may have a profound contribution to freezing in PD.

The activation of a population of hippocampal neurons thought to encode a specific fear memory is shown to elicit freezing behaviour in mice. Neural representation of a memory Several studies have used ablation strategies to demonstrate that certain neuronal populations in the brain are needed for memory expression, but whether a particular ensemble is sufficient to elicit a behavioural outcome from a particular memory has remained unexplored. Now, Susumu Tonegawa and colleagues use optogenetics to demonstrate that a particular, targeted memory 'engram', or group of cells, that was active during fear-learning is sufficient to drive freezing behaviour in mice during subsequent reactivations. A specific memory is thought to be encoded by a sparse population of neurons 1 , 2 . These neurons can be tagged during learning for subsequent identification 3 and manipulation 4 , 5 , 6 . Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) 7 , 8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

Conditioned fear memory, once formed through fear conditioning, is modulated by reexposure of individuals to a conditioned stimulus. The reexposure reactivates the fear memory, which induces reconsolidation of the memory first, and then extinction of the fear response. Both attenuating the former and facilitating the latter are effective in reducing the fear response, and these findings are potentially translatable to the enhancement of exposure therapy for complex anxiety disorders. Currently, there is no drug that is established to modulate either reconsolidation or extinction selectively, which are thought to be independent processes. Here, we report that an extinction-facilitating AMPA potentiator, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), does not act on the reconsolidation of fear memory formed by contextual fear conditioning in mice. The freezing rates observed in contextually conditioned mice following short reexposure (3 min) to the context were not influenced by intraperitoneal or intra-amygdala administration of PEPA. The same short reexposure to the context enhanced freezing responses in mice that were similarly administered D -cycloserine (DCS), a drug that facilitates both extinction and reconsolidation, and this enhancement of freezing responses in mice intraperitoneally administered DCS was abolished by propranolol, a drug that suppresses reconsolidation. At the same doses used in the short reexposure experiments, PEPA and DCS facilitated extinction of the fear response induced by long reexposure to the context and suppressed reinstatement of the conditioned fear memory. PEPA and DCS did not affect reextinction. These results suggest that PEPA acts on extinction of contextual fear memory without having detectable influences on its reconsolidation.

Freezing of gait (FOG) is one of the most disabling symptoms in Parkinsonism. Open-label studies have suggested that intravenous (IV) amantadine is effective against FOG resistant to dopaminergic therapy in Parkinson's disease (PD). We evaluated the efficacy of IV amantadine on FOG resistant to dopaminergic therapy. This was a randomized, double-blind, placebo-controlled, cross-over study on IV amantadine. The placebo (normal saline) and amantadine (400 mg/day) were injected for 2 days with a 52-hour washout period. The instruments for the outcome measures were the Freezing of Gait Questionnaire (FOGQ), Unified Parkinson's disease rating Scale (UPDRS), and the duration of the 4×10 m walking test. The placebo arm was compared to the amantadine arm. Ten patients were enrolled but two patients withdrew, one from each arm. The FOGQ and UPDRS scores and the duration of the 4×10 m walking test improved in both arms compared to the baseline (P<0.05 in all). However, there were no differences in these values between the amantadine arm and placebo arm (P = 0.368, P = 0.583, P = 0.206, respectively). Follow-up measures 2 weeks after discharge in an open-label study showed the beneficial effects of an amantadine tablet on FOG (FOGQ, P = 0.018; UPDRS, P = 0.012 respectively). This double blind, placebo-controlled study did not show the efficacy of IV amantadine on FOG when compared with the placebo. This study provides Class II evidence due to small sample size for the lack of benefit of IV amantadine on FOG resistant to dopaminergic therapy Clinicaltrials.gov NCT01313819.

Switching between exploratory and defensive behaviour is fundamental to survival of many animals, but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in mice, we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting memory or expression of behaviour. Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear behaviour. Tripping the 'fear switch' For many animals, an ability to switch from a 'normal' bold or exploratory approach to a situation to a more defensive approach when prudent is an important survival aid. Much is known about the role of entire brain areas in such processes, but what happens at the level of neuronal circuits is less well understood. 'Fear extinction' and 'renewal', two processes in which learned fearful responses to stimuli associated with unpleasant consequences are unlearned, then renewed, are effective models for probing mechanisms associated with changes in behavioural state. Herry et al . show that changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala can trigger transitions between states of high and low fear in mice. Likhtik et al . report another mechanism for 'unlearning' fearful memories, this time in rats. Amygdala cells known as intercalated neurons, which receive information from the basolateral amygdala, appear to be responsible in this case. This work suggests possible new avenues for the treatment of anxiety disorders. Changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala trigger transitions between states of high and low fear in mice. The two populations of neurons tend to participate in different anatomical circuits, suggesting that even within a single brain area, selective activation of specific neuronal circuits can trigger large changes in behavioral state.

The infralimbic (IL) division of the medial prefrontal cortex (mPFC) is a crucial site for the extinction of conditioned fear memories in rodents. Recent work suggests that neuronal plasticity in the IL that occurs during (or soon after) fear conditioning enables subsequent IL-dependent extinction learning. We therefore hypothesized that pharmacological activation of the IL after fear conditioning would promote the extinction of conditioned fear. To test this hypothesis, we characterized the effects of post-conditioning infusions of the GABA A receptor antagonist, picrotoxin, into the IL on the extinction of auditory conditioned freezing in male and female rats. In four experiments, we found that picrotoxin injections performed immediately, 24 h, or 13 days after fear conditioning reduced conditioned freezing to the auditory conditioned stimulus (CS) during both extinction training and extinction retrieval; this effect was observed up to two weeks after picrotoxin infusions. Interestingly, inhibiting protein synthesis inhibition in the IL immediately after fear conditioning prevented the inhibition of freezing by picrotoxin injected 24 h later. Our data suggest that the IL encodes an inhibitory memory during the consolidation of fear conditioning that is necessary for future fear suppression.

Fear extinction, the laboratory basis of exposure therapy for anxiety disorders, fluctuates across the female rat estrous cycle, where extinction is enhanced during proestrus (high estradiol and progesterone), and impaired during metestrus (low estradiol and progesterone). During the estrous cycle increasing levels of estradiol precede and then overlap with increased levels of progesterone. We sought to isolate the impact of these hormonal changes on fear extinction by systematically treating ovariectomized female rats with estradiol alone, or in combination with progesterone. We found that estradiol alone facilitated extinction recall, whereas the effects of progesterone on estradiol-treated rats were biphasic and dependent on the time interval between progesterone administration and extinction training. Progesterone potentiated estradiol's facilitation of extinction recall when extinction training occurred 6 h after progesterone administration. However, progesterone abolished estradiol's facilitation of extinction recall when extinction training occurred 24 h after progesterone administration. Furthermore, in naturally cycling rats, blocking progesterone receptor activation during proestrus (when progesterone levels peak) prevented the impairment in extinction recall in rats extinguished during metestrus. These results suggest that in naturally cycling females whereas cyclical increases in estradiol facilitate fear extinction, cyclical increases in progesterone may lead to fear extinction impairments. As extinction training took place after the hormonal treatments had been metabolized, we propose that genomic mechanisms may at least partly mediate the impact of cyclic fluctuations in sex hormones on fear extinction.

Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shock-mediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

The peptide hormone ghrelin has previously been linked to the regulation of metabolism. This study in mice finds that increasing levels of ghrelin, either through subcutaneous injections or calorie restriction, has an anxiolytic and antidepressive effect. This reveals a previously unknown function for ghrelin. We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor ( Ghsr ) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.

Tripping the 'fear switch' For many animals, an ability to switch from a 'normal' bold or exploratory approach to a situation to a more defensive approach when prudent is an important survival aid. Much is known about the role of entire brain areas in such processes, but what happens at the level of neuronal circuits is less well understood. 'Fear extinction' and 'renewal', two processes in which learned fearful responses to stimuli associated with unpleasant consequences are unlearned, then renewed, are effective models for probing mechanisms associated with changes in behavioural state. Herry et al . show that changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala can trigger transitions between states of high and low fear in mice. Likhtik et al . report another mechanism for 'unlearning' fearful memories, this time in rats. Amygdala cells known as intercalated neurons, which receive information from the basolateral amygdala, appear to be responsible in this case. This work suggests possible new avenues for the treatment of anxiety disorders. Although fearful responses to stimuli associated with unpleasant consequences are quickly learned, they can also be unlearned. This unlearning process, called 'extinction', is thought to depend on plastic changes in the amygdala. A specific population of amygdala cells (intercalated neurons) that are responsible for this unlearning have been pinpointed. Selective destruction of this cell type with a toxin leads to a corresponding decrease in the extinction of learned fear memories. Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders 1 , 2 , 3 , 4 . In mammals, repeated presentations of a conditioned stimulus that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala 1 , 2 , 3 , 4 , 5 , 6 , 7 , the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute probable mediators of extinction because they receive information about the conditioned stimulus from the basolateral amygdala (BLA) 8 , 9 , and contribute inhibitory projections to the central nucleus (CEA) 10 , 11 , the main output station of the amygdala for conditioned fear responses 12 . Thus, after extinction training, ITC cells could reduce the impact of conditioned-stimulus-related BLA inputs to the CEA by means of feed-forward inhibition. Here we test the hypothesis that ITC neurons mediate extinction by lesioning them with a toxin that selectively targets cells expressing µ-opioid receptors (µORs). Electron microscopic observations revealed that the incidence of µOR-immunoreactive synapses is much higher in ITC cell clusters than in the BLA or CEA and that µORs typically have a post-synaptic location in ITC cells. In keeping with this, bilateral infusions of the µOR agonist dermorphin conjugated to the toxin saporin in the vicinity of ITC neurons caused a 34% reduction in the number of ITC cells but no significant cell loss in surrounding nuclei. Moreover, ITC lesions caused a marked deficit in the expression of extinction that correlated negatively with the number of surviving ITC neurons but not CEA cells. Because ITC cells exhibit an unusual pattern of receptor expression, these findings open new avenues for the treatment of anxiety disorders.