Investigating the role of CB1 endocannabinoid transmission in the anti-fear and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation.

Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) of rats induces anti-fear and anxiolytic-like behaviours, while reducing principal cell firing in the basolateral amygdala (BLA). In parallel, the endocannabinoid system, particularly in the vmPFC and BLA, has emerged as a target for the amelioration of fear and stress-related behaviours. We tested whether DBS-related improvements in fear and anxiety-type behaviour are mediated by endocannabinoid signalling. First, we examined type-1 cannabinoid (CB1) receptor and fatty acid amide hydrolase (FAAH) expression in the vmPFC and BLA and found reduced CB1 expression in both loci in rats treated with DBS. Next, we conducted pharmacological experiments to test whether the inverse CB1 agonist AM251 could mitigate the behavioural effects of stimulation. Chronic vmPFC DBS was delivered to rats following conditioning and extinction. Animals were then tested for extinction recall and anxiety-type behaviour following the systemic administration of AM251 or vehicle. We found that DBS reduced freezing and induced anxiolytic-type effects in defensive burying and novelty supressed feeding paradigms. These responses were not countered by CB1 antagonism, suggesting that other mechanisms may be involved in the anti-fear and anxiolytic effects of DBS.

Intact Behavioral Expression of Contextual Fear, Context Discrimination, and Object Discrimination Memories Acquired in the Absence of the Hippocampus.

We test the hypothesis that the stability and precision of context and visual discrimination memories depend on interactions between the hippocampus (HPC) and other memory storage networks. In four experiments we tested the properties of memories acquired in the absence of the HPC. Long-Evans male rats were exclusively used in all experiments. Experiment 1 evaluated acquisition and retention of context fear memories in rats with prior partial or complete HPC damage. Confirming an earlier report (Zelikowsky et al., 2012) a very small but statistically reliable slowing in a single session of context fear conditioning was found after HPC damage. In contrast, retention of context fear memory was normal after HPC damage up to 30 d after learning. In experiment 2, we found that discrimination between a context paired with foot shocks and a different context never paired with foot shock was retained normally for 15 d. In experiment 3, we replicated the finding of intact context discrimination for at least 15 d in rats who display a significant impairment in acquisition of place learning in the Morris water task (MWT). In final experiment using an appetitive object discrimination task, we showed normal retention of the discrimination for at least 30 d after training in rats with complete HPC damage. These finding score against the idea that non HPC memory storage requires a period of interaction with HPC to establish a stable, precise memory.SIGNIFICANCE STATEMENT Contrary to expectations from systems memory consolidation, we find that in the absence of a functional hippocampus (HPC) context and visual memories are formed rapidly and exhibit normal persistence and precision. The findings suggest that the HPC is not obligatory for these features of long-term memories.

Endocannabinoid modulating drugs improve anxiety but not the expression of conditioned fear in a rodent model of post-traumatic stress disorder.

The endocannabinoid (eCB) system is a potential target for the treatment of symptoms of post-traumatic stress disorder (PTSD). Similar to clinical PTSD, approximately 25-30% of rats that undergo cued fear conditioning exhibit impaired extinction learning. In addition to extinction-resistant fear, these "weak extinction" (WE) rats show persistent anxiety-like behaviors. The goal of the present study was to test the hypothesis that behavioural differences between WE animals and those presenting normal extinction patterns (strong extinction; SE) could be mediated by the eCB system. Rats undergoing fear conditioning/extinction and fear recall sessions were initially segregated in weak and strong-extinction groups. Two weeks later, animals underwent a fear recall session followed by a novelty-suppressed feeding (NSF) test. In acute experiments, WE rats were injected with either the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the CB1 agonist WIN55,212-2 1 h prior to long-term recall and NSF testing. SE animals were injected with the inverse CB1 receptor agonist AM251. In chronic experiments, WE and SE rats were given daily injections of URB597 or AM251 between short and long-term recall sessions. We found that acute administration of WIN55,212-2 but not URB597 reduced anxiety-like behaviour in WE rats. In contrast, AM251 was anxiogenic in SE animals. Neither treatment was effective in altering freezing expression during fear recall. The chronic administration of AM251 to SE or URB597 to WE did not alter fear or anxiety-like behaviour or changed the expression of FAAH and CB1. Together, these results suggest that systemic manipulations of the eCB system may alter anxiety-like behaviour but not the behavioural expression of an extinction-resistant associative fear memory.

Anodal transcranial direct current stimulation with monopolar pulses improves limb use after stroke by enhancing inter-hemispheric coherence.

Post-stroke neurological deficits, such as sensorimotor impairments, are often permanent and a leading cause of disability. Stroke is also associated with changes in neuronal synchrony among different brain areas. Multiple studies demonstrated that non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS), enhances the efficacy of existing rehabilitative therapies. We hypothesized that the therapeutic effects of tDCS could be due to its influence on neuronal synchrony. To study this, we recorded local field potentials in rats treated with anodal tDCS (a-tDCS) after unilateral ischemic motor cortex lesion. To enhance the effect of a-tDCS on neuronal synchrony, we added monopolar pulses (a-tDCSmp) during a treatment. We found that ischemic lesions reduced interhemispheric coherence in the low gamma frequency range. By contrast, a-tDCSmp treatment increased interhemispheric coherence along with motor improvement in a skilled reaching task. These observations indicate that increased neuronal coherence is a likely mechanism by which tDCS improves stroke recovery. Moreover, this work adds to previous evidence that measures of brain coherence could be used as a biomarker of stroke recovery, which may help in the design of more effective tDCS protocols for stroke rehabilitation.

Neuromodulation Strategies in Post-Traumatic Stress Disorder: From Preclinical Models to Clinical Applications.

Post-traumatic stress disorder (PTSD) is an often debilitating disease with a lifetime prevalence rate between 5⁻8%. In war veterans, these numbers are even higher, reaching approximately 10% to 25%. Although most patients benefit from the use of medications and psychotherapy, approximately 20% to 30% do not have an adequate response to conventional treatments. Neuromodulation strategies have been investigated for various psychiatric disorders with promising results, and may represent an important treatment option for individuals with difficult-to-treat forms of PTSD. We review the relevant neurocircuitry and preclinical stimulation studies in models of fear and anxiety, as well as clinical data on the use of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) for the treatment of PTSD.

Barriers to developing a valid rodent model of Alzheimer's disease: from behavioral analysis to etiological mechanisms.

Sporadic Alzheimer's disease (AD) is the most prevalent form of age-related dementia. As such, great effort has been put forth to investigate the etiology, progression, and underlying mechanisms of the disease. Countless studies have been conducted, however, the details of this disease remain largely unknown. Rodent models provide opportunities to investigate certain aspects of AD that cannot be studied in humans. These animal models vary from study to study and have provided some insight, but no real advancements in the prevention or treatment of the disease. In this Hypothesis and Theory paper, we discuss what we perceive as barriers to impactful discovery in rodent AD research and we offer potential solutions for moving forward. Although no single model of AD is capable of providing the solution to the growing epidemic of the disease, we encourage a comprehensive approach that acknowledges the complex etiology of AD with the goal of enhancing the bidirectional translatability from bench to bedside and vice versa.

Dose-dependent loss of motor function after unilateral medial forebrain bundle rotenone lesion in rats: a cautionary note.

The organic pesticide rotenone is a neurotoxin suspected to cause Parkinson's disease (PD) symptoms by selectively targeting and compromising the survival of dopaminergic neurons. Rotenone in rodent models reproduces key features of human PD by impairing the mitochondrial electron transport chain, leading to intracellular alpha-synuclein aggregates and functional impairments typical for PD. The present study characterized the dose-response relationship of standard rotenone concentrations in motor impairments in a rat model. Rats received a single medial forebrain bundle injection of 4, 8, or 12µg of rotenone. Animals were assessed in skilled limb use, skilled and non-skilled walking and exploratory activity as well as drug-induced rotation. The results revealed rotational bias and stable impairments in skilled walking and gross motor function up to five weeks post injection. However, transient motor deficits facilitated rapid improvement of skilled reaching success. Mainly the temporal aspects of skilled and non-skilled motor performance were responsive to different rotenone concentrations. By contrast, drug-induced rotation and nigral TH+ cell loss were not influenced by different rotenone doses. Rats infused with 8µg and 12µg seemed to have reached a ceiling effect in motor deficits as they were not distinguishable in behavioral measures. Most strikingly, the stereological and morphological analyses revealed non-specific toxicity of vehicle and rotenone infusions that caused macroscopic lesions beyond nigral boundaries. These findings suggest that sensitivity of comprehensive motor tests to subtle modulation of dopamine function is independent of dopamine cell loss per se. Furthermore, caution is advised concerning non-specific toxicity of rotenone and vehicle substances in experimental animal models.