Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.

Jacques Jean Lhermitte and Lhermitte's sign.

Jacques Jean Lhermitte, a forefather of modern clinical neurology, was a French neurologist conducting the majority of his research between 1908 and 1957. Although less well known than his contemporaries at the time, Lhermitte eventually was famously recognized for his eponymously named "Lhermitte's sign." Lhermitte's contributions to the field of neurology spanned that of monographic clinical descriptions of syndromes to exquisitely detailed descriptions of neuropathology, finally delving into the realm of modern neuropsychiatry in his later years. Lhermitte laid the groundwork for the burgeoning field of neurology, developing the reputation of a renaissance physician by both his contemporaries and current neurologists. Here, we take an extensive look into the life and career of Lhermitte and the legacies that he left behind.

Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.

Dendritic cells (DCs) and macrophages (Møs) internalize and process exogenous HIV-derived antigens for cross-presentation by MHC-I to cytotoxic CD8⁺ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Møs. The cross-presentation of HIV proteins by both DCs and Møs led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mø cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross-presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross-presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation.

Gaetano Perusini: The Forgotten Neuroscientist Behind "Alzheimer's" Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment with social and occupational impacts. This form of dementia is being increasingly studied, and its prevalence is expected to rise in the near future. Gaetano Perusini, a neuroscientist in the Alzheimer's laboratory, has played a major clinical and pathological role in the earlier study of Alzheimer's disease. This article summarizes his role in the discovery of the disease, which should be fairly named Alzheimer-Perusini disease.

Pliny the Elder: Lessons from the Naturalist as an Early Neuroscientist.

Pliny the Elder was a prolific Roman author, naturalist, and military leader. Yet, his impact on modern-day neuroscience, psychiatry, and neurology has been little explored. Here, we aimed to trace the origins of our current understanding of the brain in ancient Rome through Pliny and his work, Natural History. As his magnum opus, this 37-book tome catalogs the facts and observations of natural life collected by Pliny, reflecting the knowledge of his time. Following the cephalocentric school of thought, Pliny places the brain as an agent for consciousness and details its diseases. Further, we explore Pliny's methods, which allow him to build a thorough collection of clinical descriptions and remedies. This body of work serves as an important lesson for future neuroscientists on the power of observation, the role of the humanities, and the necessity of understanding the origin of modern scientific thinking.

In vivo spatiotemporal control of voltage-gated ion channels by using photoactivatable peptidic toxins.

Photoactivatable drugs targeting ligand-gated ion channels open up new opportunities for light-guided therapeutic interventions. Photoactivable toxins targeting ion channels have the potential to control excitable cell activities with low invasiveness and high spatiotemporal precision. As proof-of-concept, we develop HwTxIV-Nvoc, a UV light-cleavable and photoactivatable peptide that targets voltage-gated sodium (NaV) channels and validate its activity in vitro in HEK293 cells, ex vivo in brain slices and in vivo on mice neuromuscular junctions. We find that HwTxIV-Nvoc enables precise spatiotemporal control of neuronal NaV channel function under all conditions tested. By creating multiple photoactivatable toxins, we demonstrate the broad applicability of this toxin-photoactivation technology.

Neurologic complications of Down syndrome: a systematic review.

Down syndrome (DS) is one of the most well-recognized genetic disorders. Persons with DS are known to have a variety of co-morbid medical problems, affecting nearly all organ systems. Improved healthcare interventions and research have allowed for increased life span of persons with DS, although disorders of the neurologic system remain underexplored. The purpose of this systematic review is to provide clinically pertinent information on the neurological phenotypes of frequently occurring or clinically relevant conditions. A retrospective review of MEDLINE, Scopus, and Pubmed were used to identify sources among seventeen, clinically relevant, search categories. MeSH terms all contained the phrase "Down Syndrome" in conjunction with the topic of interest. 'Frequently-occurring' was defined as prevalent in more than 10% of persons with DS across their lifespan, whereas 'clinically-relevant' was defined as a disease condition where early diagnosis or intervention can augment the disease course. In total, 4896 sources were identified with 159 sources meeting criteria for inclusion. Seventeen clinical conditions were grouped under the following subjects: hypotonia, intellectual and learning disability, cervical instability, autism spectrum disorder, epilepsy, cerebrovascular disease, Alzheimer's disease and neuropsychiatric disease. The results of this review provide a blueprint for the clinical neurologist taking care of persons with DS across the age spectrum and indicate that there are many underrecognized and misdiagnosed co-occurring conditions in DS, highlighting the need for further research.

Obesity is associated with the Optic Neuritis severity in Male patients with Multiple Sclerosis.

BACKGROUND: Obesity is an important modifiable risk factor of MS; a deeper biological understanding of this association is needed. OBJECTIVE: To evaluate the determinants of acute optic neuritis (AON) severity and recovery in multiple sclerosis (MS). METHODS: We included 61 patients with MS with recorded AON severity and recovery according to visual acuity outcomes before, at, and, after the relapse. We measured body mass index (BMI) and the serum concentration of estrogen, leptin, testosterone, sex hormone-binding globulin, and vitamin D. We tested the association between BMI and serum hormones and AON severity and recovery with logistic regressions. RESULTS: In males, moderate/severe AON was associated with higher BMI (31.26 kg/m2 vs 25.73 kg/m2, logistic regression, p= 0.03), higher serum estrogen levels (32.24 nmol/L vs 23.06 nmol/L, logistic regression, p=0.04), and higher serum leptin levels (12.29 ng/mL vs mild AON: 4.1 ng/mL, logistic regression, p=0.06) than mild AON. These observations were not seen in female patients. We did not find an association with BMI or hormone levels and AON recovery. CONCLUSION: BMI, serum leptin, and serum estrogen were associated with AON severity in male patients but not in female patients. No association of these factors and AON recovery was observed.

Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.

The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

Targeting Kruppel-like Factor 9 in Excitatory Neurons Protects against Chronic Stress-Induced Impairments in Dendritic Spines and Fear Responses.

Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.