Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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Brain µ-opioid receptors (MOR) mediate reward and help coping with pain, social rejection, anxiety and depression. The dorsal midline thalamus (dMT) integrates visceral/emotional signals and biases behavior towards aversive or defensive states through projections to the amygdala. While a dense MOR expression in the dMT has been described, the exact cellular and synaptic mechanisms of µ-opioidergic modulation in the dMT-amygdala circuitry remain unresolved. Here, we hypothesized that MORs are important negative modulators of dMT-amygdala excitatory networks. Using retrograde tracers and targeted channelrhodopsin expression in combination with patch-clamp electrophysiology, we found that projections of dMT neurons onto both basal amygdala principal neurons (BA PN) and central amygdala (CeL) neurons are attenuated by stimulation of somatic or synaptic MORs. Importantly, dMT efferents to the amygdala drive feedforward excitation of centromedial amygdala neurons (CeM), which is dampened by MOR activation. This downregulation of excitatory activity in dMT-amygdala networks puts the µ-opioid system in a position to ameliorate aversive or defensive behavioral states associated with stress, withdrawal, physical pain or social rejection.

The present work studies whether chronic prenatal stress (PS) influences the long-term sex-dependent neuropsychological status of offspring and the effects of an early dietary intervention in the dam. In addition, dams were fed with either a high-fat sugar diet (HFSD) or methyl donor supplemented diet (MDSD). PS procedure did not affect body weight of the offspring. MDSD induced decreases in body weight both in male and female offspring (1 month) that were still present in aged rats. HFSD induced an increase in body weight both in male and female offspring that did not persist in aged rats. In the Porsolt forced swimming test, only young males showed increases in immobility time that were reversed by MDSD. In old female rats (20 months), PS-induced cognitive impairment in both the novel object recognition test (NORT) and in the Morris water maze that was reversed by MDSD, whereas in old males, cognitive impairments and reversion by MDSD was evident only in the Morris water maze. HFSD induced cognitive impairment in both control and PS old rats, but there was no additive effect of PS and HFSD. It is proposed here that the diversity of symptoms following PS could arise from programming effects in early brain development and that these effects could be modified by dietary intake of the dam.

Background: Nuclei located in the dorsal midline thalamus, such as the paraventricular nucleus of the thalamus (PVT), are crucial to modulate fear and aversive behaviour. In addition, the PVT shows a dense expression of µ-opioid receptors (MORs) and could mediate the anxiolytic effects of opioids. Methods: We analysed the contribution of MORs in the dorsal midline thalamus (i.e. the PVT) to the performance of mice in a classical fear conditioning paradigm. We locally injected a specific agonist (DAMGO), an antagonist (CTAP) of MOR or saline as a control into the dorsal midline thalamus of male mice, prior to fear extinction training. We assessed freezing as a typical measure of fear and extended our analysis by evaluation of aversive, non-aversive and neutral behavioural features using compositional data analysis. Results: Pharmacological blockade of MORs through CTAP in the dorsal midline thalamus induced a fear memory extinction deficit, as evidenced by maintained freezing during extinction sessions. Stimulation of MORs by DAMGO resulted in an overall increase in locomotor activity, associated with decreased freezing during recall of extinction. Compositional data analysis confirmed the freezing-related pharmacological effects and revealed specific differences in basic behavioural states. CTAP-treated mice remained in an aversive state, whereas DAMGO-treated mice displayed predominantly neutral behaviour. Conclusions: Fear extinction requires the integrity of the µ-opioid system in the dorsal midline thalamus. Pharmacological stimulation of MOR and associated facilitation of fear extinction recall suggest a potential therapeutic avenue for stress-related or anxiety disorders.