A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age.

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

Male and female rats show opiate withdrawal-induced place aversion and extinction in a Y-maze paradigm.

Gender differences have been observed in the vulnerability to drug abuse and in the different stages of the addictive process. In opiate dependence, differences between sexes have been shown in humans and laboratory animals in various phases of opiate addiction, especially in withdrawal-associated negative affective states. Using a Y-maze conditioned place aversion paradigm, we investigated potential sex differences in the expression and extinction of the aversive memory of precipitated opiate withdrawal state in morphine-dependent rats. No significant difference between sexes was observed in the occurrence of withdrawal signs following naloxone injection during conditioning. Moreover, opiate withdrawal memory expression and extinction following repeated testing was demonstrated in both male and female rats, with no significant differences between sexes. Finally, we report spontaneous recovery following extinction of opiate withdrawal memory. Altogether these data provide further evidence that persistent withdrawal-related memories may be strong drivers of opiate dependence, and demonstrate that both males and females can be used in experimental rodent cohorts to better understand opiate-related effects, reward, aversive state of withdrawal, abstinence and relapse.

Survival and risk of COVID-19 after SARS-COV-2 vaccination in a series of 2391 cancer patients.

BACKGROUND: Patients with cancer are at high risk of severe or lethal COVID-19. The impact of SARS-COV-2 vaccination on the risk of developing COVID-19 was investigated in an exhaustive series of patients from a comprehensive cancer center. METHODS: This is a study of the exhaustive population of 2391 cancer patients who were prescribed SARS-COV-2 vaccination until 09/21. Patient characteristics, documented SARS-COV-2 infection with RT-PCR, and survival were collected. The primary endpoint was the rate of COVID-19 after vaccination. Secondary endpoints included risk factors to develop COVID-19 after vaccination, with a comparison with the cohort of vaccinated health care workers (HCW), and risk factors for death. RESULTS: From January to September 2021, among 2391 patients with cancer under active treatment in whom a SARS-COV-2 vaccine was prescribed, 659 (28%), 1498 (63%) and 139 (6%) received 1, 2, and 3 doses, respectively. Ninety five patients received a single dose of vaccine after a previous COVID-19. Two thousand two hundred eighty five health care workers (HCW) received one (N = 17, 0.7%), 2-3 (N = 2026, 88.7%) vaccine doses and one dose after COVID-19 (N = 242, 10.6%). With a median follow-up of 142 and 199 days for patients and HCW, respectively. Thirty nine (1.6%) patients and 35 (1.5%) HCW developed COVID-19 after vaccination. Six of 39 cancer patients and no HCW died because ofCOVID-19 within 50 days after diagnosis. Independent risk factors for COVID-19 in vaccinated patients were age, single dose of vaccine without previous COVID-19 and anti-CD20 treatment in the last three months. Independent risk factors for death included metastatic disease, gender, cancer type, but also documented COVID-19 before vaccination. CONCLUSIONS: Patients receiving two or more doses of COVID-19 vaccine have reduced risk of COVID-19. The risk of death of vaccinated cancer patients presenting COVID-19 remains high. COVID-19 before vaccination is associated with an increased overall risk of death.

Impact of acute and chronic nicotine administration on midbrain dopaminergic neuron activity and related behaviours in TRPV1 knock-out juvenile mice.

The addictive properties of nicotine, the main alkaloid in tobacco and tobacco-derived products, largely depend on its action on the activity of midbrain dopamine (DA) neurons. The transient receptor potential vanilloid 1 (TRPV1) channel has also been examined as an emerging contributor to addiction-related symptoms due to its ability to modulate midbrain neurons. Thus, the objective of our study was to explore the role of TRPV1 receptors (TRPV1Rs) on nicotine-induced behaviours and associated response of DA neuron activity. Both wild type juvenile mice and juvenile mice with invalidation of the TRPV1R gene were exposed to acute or chronic nicotine 0.3 mg/kg administration. We analysed locomotor activity in response to the drug. In addition, we performed cell-attached and whole-cell recordings from ventral tegmental area (VTA) neurons after nicotine exposure. Our results showed that the genetic deletion of TRPV1Rs reduced nicotine-induced locomotor sensitization. In addition, it provided evidence in support of TRPV1Rs being regulators of inhibitory synaptic transmission in the VTA. However, TRPV1Rs did not seem to modulate either nicotine-induced conditioning place preference or nicotine-evoked electrical activity of DA neurons. In conclusion, TRPV1Rs modulate nicotine-induced psychomotor sensitization in mice independently of a control on VTA DA neuron activity. Thus, TRPV1R control may depend on another key player of the mesolimbic circuit.

Contusion Rodent Model of Traumatic Brain Injury: Controlled Cortical Impact.

Traumatic brain injury (TBI) is a heterogeneous brain injury which represents one of the leading causes of mortality and disability worldwide. Rodent TBI models are helpful to examine the cellular and molecular mechanisms after injury. Controlled cortical impact (CCI) is one of the most commonly used TBI models in rats and mice, based on its consistency of injury and ease of implementation. Here, we describe a CCI protocol to induce a moderate contusion to the somatosensory motor cortex. We provide additional protocols for monitoring animals after CCI induction.

High mortality rate in cancer patients with symptoms of COVID-19 with or without detectable SARS-COV-2 on RT-PCR.

BACKGROUND: Cancer patients presenting with COVID-19 have a high risk of death. In this work, predictive factors for survival in cancer patients with suspected SARS-COV-2 infection were investigated. METHODS: PRE-COVID-19 is a retrospective study of all 302 cancer patients presenting to this institute with a suspicion of COVID-19 from March 1st to April 25th 2020. Data were collected using a web-based tool within electronic patient record approved by the Institutional Review Board. Patient characteristics symptoms and survival were collected and compared in SARS-COV-2 real-time or reverse-transcriptase PCR (RT-PCR)-positive and RT-PCR-negative patients. RESULTS: Fifty-five of the 302 (18.2%) patients with suspected COVID-19 had detectable SARS-COV-2 with RT-PCR in nasopharyngeal samples. RT-PCR-positive patients were older, had more frequently haematological malignancies, respiratory symptoms and suspected COVID-19 pneumonia of computed tomography (CT) scan. However, respectively, 38% and 20% of SARS-COV-2 RT-PCR-negative patients presented similar respiratory symptoms and CT scan images. Thirty of the 302 (9.9%) patients died during the observation period, including 24 (80%) with advanced disease. At the median follow-up of 25 days after the first symptoms, the death rate in RT-PCR-positive and RT-PCR-negative patients were 21% and 10%, respectively. In both groups, independent risk factors for death were male gender, Karnofsky performance status <60, cancer in relapse and respiratory symptoms. Detection of SARS-COV-2 on RT-PCR was not associated with an increased death rate (p = 0.10). None of the treatment given in the previous month (including cytotoxics, PD1 Ab, anti-CD20, VEGFR2…) correlated with survival. The survival of RT-PCR-positive and -negative patients with respiratory symptoms and/or COVID-19 type pneumonia on CT scan was similar with a 18.4% and 19.7% death rate at day 25. Most (22/30, 73%) cancer patients dying during this period were RT-PCR negative. CONCLUSION: The 30-day death rate of cancer patients with or without documented SARS-COV-2 infection is poor, but the majority of deaths occur in RT-PCR-negative patients.

Early cerebrovascular and long-term neurological modifications ensue following juvenile mild traumatic brain injury in male mice.

Clinical evidence suggests that a mild traumatic brain injury occurring at a juvenile age (jmTBI) may be sufficient to elicit pathophysiological modifications. However, clinical reports are not adequately integrated with experimental studies examining brain changes occurring post-jmTBI. We monitored the cerebrovascular modifications and assessed the long-term behavioral and electrographic changes resulting from experimental jmTBI. In vivo photoacoustic imaging demonstrated a decrease of cerebrovascular oxygen saturation levels in the impacted area hours post-jmTBI. Three days post-jmTBI oxygenation returned to pre-jmTBI levels, stabilizing at 7 and 30 days after the injury. At the functional level, cortical arterioles displayed no NMDA vasodilation response, while vasoconstriction induced by thromboxane receptor agonist was enhanced at 1 day post-jmTBI. Arterioles showed abnormal NMDA vasodilation at 3 days post-jmTBI, returning to normality at 7 days post injury. Histology showed changes in vessel diameters from 1 to 30 days post-jmTBI. Neurological evaluation indicated signs of anxiety-like behavior up to 30 days post-jmTBI. EEG recordings performed at the cortical site of impact 30 days post-jmTBI did not indicate seizures activity, although it revealed a reduction of gamma waves as compared to age matched sham. Histology showed decrease of neuronal filament staining. In conclusion, experimental jmTBI triggers an early cerebrovascular hypo­oxygenation in vivo and faulty vascular reactivity. The exact topographical coherence and the direct casualty between early cerebrovascular changes and the observed long-term neurological modifications remain to be investigated. A potential translational value for cerebro-vascular oxygen monitoring in jmTBI is discussed.

Juvenile mild traumatic brain injury elicits distinct spatiotemporal astrocyte responses.

Mild-traumatic brain injury (mTBI) represents ~80% of all emergency room visits and increases the probability of developing long-term cognitive disorders in children. To date, molecular and cellular mechanisms underlying post-mTBI cognitive dysfunction are unknown. Astrogliosis has been shown to significantly alter astrocytes' properties following brain injury, potentially leading to significant brain dysfunction. However, such alterations have never been investigated in the context of juvenile mTBI (jmTBI). A closed-head injury model was used to study jmTBI on postnatal-day 17 mice. Astrogliosis was evaluated using glial fibrillary acidic protein (GFAP), vimentin, and nestin immunolabeling in somatosensory cortex (SSC), dentate gyrus (DG), amygdala (AMY), and infralimbic area (ILA) of prefrontal cortex in both hemispheres from 1 to 30 days postinjury (dpi). In vivo T2-weighted-imaging (T2WI) and diffusion tensor imaging (DTI) were performed at 7 and 30 dpi to examine tissue level structural alterations. Increased GFAP-labeling was observed up to 30 dpi in the ipsilateral SSC, the initial site of the impact. However, vimentin and nestin expression was not perturbed by jmTBI. The morphology of GFAP positive cells was significantly altered in the SSC, DG, AMY, and ILA up to 7 dpi that some correlated with magnetic resonance imaging changes. T2WI and DTI values were significantly altered at 30 dpi within these brain regions most prominently in regions distant from the impact site. Our data show that jmTBI triggers changes in astrocytic phenotype with a distinct spatiotemporal pattern. We speculate that the presence and time course of astrogliosis may contribute to pathophysiological processes and long-term structural alterations following jmTBI.

Arc reactivity in accumbens nucleus, amygdala and hippocampus differentiates cue over context responses during reactivation of opiate withdrawal memory.

Opiate withdrawal induces an early aversive state which can be associated to contexts and/or cues, and re-exposure to either these contexts or cues may participate in craving and relapse. Nucleus accumbens (NAC), hippocampus (HPC) and basolateral amygdala (BLA) are crucial substrates for acute opiate withdrawal, and for withdrawal memory retrieval. Also HPC and BLA interacting with the NAC are suggested to respectively mediate the processing of context and cue representations of drug-related memories. Here we used a paradigm of conditioned suppression of operant food seeking, allowing to differentiate context and cue related responses, to study the influence of withdrawal memories on operant behavior and the underlying neural substrates. catFISH for Arc mRNA expression was used to discriminate cellular responses during context and cue (flashing light) periods in this paradigm. We show that reactivation of the memory of the negative affective state of withdrawal suppresses active lever pressing for food, and this conditioned suppression is generalized to the context. Interestingly the behavioral responses during the context and cue light periods are associated with differential Arc mRNA activations within the NAC, BLA, and HPC. Indeed both periods led to NAC shell activation whereas the NAC core was responsive only following the cue light period. Moreover, BLA and HPC were more responsive during cue-light and context period respectively. These data further support the already reported differential role of these brain structures on cue vs context-induced reinstatement of operant behaviors, and highlight the existence of common mechanisms for the processing of positive and aversive emotional memories.

Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit.

The subthalamic nucleus (STN) is a critical component of a complex network controlling motor, associative and limbic functions. High-frequency stimulation (HFS) of the STN is an effective therapy for motor symptoms in Parkinsonian patients and can also reduce their treatment-induced addictive behaviors. Preclinical studies have shown that STN HFS decreases motivation for cocaine while increasing that for food, highlighting its influence on rewarding and motivational circuits. However, the cellular substrates of these effects remain unknown. Our objectives were to characterize the cellular consequences of STN HFS with a special focus on limbic structures and to elucidate how STN HFS may interfere with acute cocaine effects in these brain areas. Male Long-Evans rats were subjected to STN HFS (130 Hz, 60 µs, 50-150 µA) for 30 min before an acute cocaine injection (15 mg/kg) and sacrificed 10 min following the injection. Neuronal reactivity was analyzed through the expression of two immediate early genes (Arc and c-Fos) to decipher cellular responses to STN HFS and cocaine. STN HFS only activated c-Fos in the globus pallidus and the basolateral amygdala, highlighting a possible role on emotional processes via the amygdala, with a limited effect by itself in other structures. Interestingly, and despite some differential effects on Arc and c-Fos expression, STN HFS diminished the c-Fos response induced by acute cocaine in the striatum. By preventing the cellular effect of cocaine in the striatum, STN HFS might thus decrease the reinforcing properties of the drug, which is in line with the inhibitory effect of STN HFS on the rewarding and reinforcing properties of cocaine.