The aging of the population, attributed to increased life expectancy, coincides with a rise in the prevalence of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. The symptoms of these disorders, such as motor disturbances and cognitive impairment, occur only after significant neurological damage, greatly diminishing the effectiveness of treatments. Consequently, achieving early diagnosis of neurodegenerative diseases stands as a paramount global health challenge. These conditions are characterized by the progressive loss of specific neuronal groups in the nervous system, resulting in dysfunction and eventual cell death in the brain. Although the exact cause of neuronal degeneration remains largely unknown, recent studies have revealed the significant involvement of the immune system in the pathogenesis of these diseases. Notably, the identification of reactive antibodies targeting specific antigens has highlighted a close association between immune mechanisms and the neurodegenerative process. Thus, the aim of this review is to explore the mechanisms of the adaptive immune system and their impact on the pathogenesis of neurodegenerative diseases, with a particular focus on reactive antibodies and their potential as diagnostic biomarkers.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices ex vivo or under different anesthetics or during wakefulness in vivo. LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes ("tonic" or "phasic"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.

Chronic pain often coexists with stress-related disorders such as anxiety and depression, with a higher prevalence in women. Rodent studies reveal significant sex differences in pain and stress-related behaviours, emphasising the need to explore underlying neurobiological mechanisms. The locus coeruleus (LC), the main noradrenergic nucleus in the brainstem, plays a crucial role in modulating pain and stress responses and exhibits sex-specific characteristics. In this study, we investigated the effects of neuropathic pain on the LC in male and female mice, focusing on sensory thresholds, emotional states, and cognitive function. Nerve injury caused immediate sensory hypersensitivity in both sexes, while depressive-like behaviours and cognitive impairments emerged only after prolonged injury. Interestingly, anxiety-like behaviours and heightened fear conditioning were exclusive to males, which correlated with specific structural and functional changes in the male LC, such as increased noradrenergic cell counts, larger somato-dendritic volume, and greater neuron excitability. In females, however, neuronal excitability was reduced. Chemogenetic inhibition of LC neurons alleviated depressive- and anxiety-like behaviours, as well as fear conditioning, but only in males. Overall, neuropathic pain induces distinct behavioural and neurobiological responses in males and females, challenging traditional views on female vulnerability to pain-induced anxiety and highlighting the need for sex-specific LC-targeted therapies. ### Competing Interest Statement The authors have declared no competing interest.

Parkinson gaixotasuna (PG) prebalentzia altua duen gaixotasun neurodegeneratiboa bada ere, sintomak hasi eta 20 urte beranduago diagnostikatzen da eta oraindik ere, ez da neuroendekapena gelditzeko tratamendu eraginkorrik aurkitu. Urte askotan zehar sintoma motorrekin lotu den gaixotasuna izan bada ere, azken hamarkadetan sistema ez-motorretan duen eragina ikertu da, besteak beste, hesteetako mikrobiotarekin izan dezakeen lotura aztertuz. Izan ere, heste-garun ardatzaren bidez hesteetako mikrobiotak gaixotasunean eragin dezakeela ikusi da, hesteetako iragazkortasuna aldatuz eta hanturazko metabolitoak sortuz, batik bat. Gainera, hesteetako disbiosiarekin edo mikrobiotaren alterazioarekin erlazionatuta, zenbait mikroorganismoen ugaritasunean aldaketak deskribatu dira dagoeneko, batez ere bakterio-genero konkretu batzuenak. Hala, mikrobiota kontrolatzeko terapiek, besteak beste, dietoterapiak, probiotikoek, antibiotikoek eta transplante fekalekin egin diren ikerketek emaitza itxaropentsuak erakutsi dituzte. Arlo honetan egindako aurrerapenek tratamendu berri eta eraginkorragoak bilatzeko atea zabaltzen dute, mikrobiota-heste-garun ardatza sakontasunez aztertzearen garrantzia bermatuz.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the subsequent motor disability. The most frequently used treatments in clinics, such as L-DOPA, restore dopaminergic neurotransmission in the brain. However, these treatments are only symptomatic, have temporary efficacy, and produce side effects. Part of the side effects are related to the route of administration as the consumption of oral tablets leads to unspecific pulsatile activation of dopaminergic receptors. For this reason, it is necessary to not only find alternative treatments, but also to develop new administration systems with better security profiles. Nanoparticle delivery systems are new administration forms designed to reach the pharmacological target in a highly specific way, leading to better drug bioavailability, efficacy and safety. Some of these delivery systems have shown promising results in animal models of PD not only when dopaminergic drugs are administered, but even more when neurotrophic factors are released. These latter compounds promote maturation and survival of dopaminergic neurons and can be exogenously administered in the form of pharmacological therapy or endogenously generated by non-pharmacological methods. In this sense, experimental exposure to enriched environments, a non-invasive strategy based on the combination of social and inanimate stimuli, enhances the production of neurotrophic factors and produces a neuroprotective effect in parkinsonian animals. In this review, we will discuss new nanodelivery systems in PD with a special focus on therapies that increase the release of neurotrophic factors.

Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer’s disease and Parkinson’s disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early stages of the disease. It is common that by the time a patient is diagnosed with the disease, the level of neurodegeneration is already severe. Thus, it is critical to find new diagnostic methods that allow earlier and more accurate disease detection. This study reviews the methods available for the clinical diagnosis of neurodegenerative diseases and potentially interesting new technologies. Neuroimaging techniques are the most widely used in clinical practice, and new techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have significantly improved the diagnosis quality. Identifying biomarkers in peripheral samples such as blood or cerebrospinal fluid is a major focus of the current research on neurodegenerative diseases. The discovery of good markers could allow preventive screening to identify early or asymptomatic stages of the neurodegenerative process. These methods, in combination with artificial intelligence, could contribute to the generation of predictive models that will help clinicians in the early diagnosis, stratification, and prognostic assessment of patients, leading to improvements in patient treatment and quality of life.

Parkinson gaixotasuna (PG) nahasmendu neurodegeneratibo motor ohikoena da, substantia nigra pars compacta-ko (SNc) neurona dopaminergikoen galeragatik eta horrek eragindako mugitzeko desgaitasunagatik bereizten dena. Klinikan gehien erabiltzen diren egungo tratamenduek, hala nola lebodopak, garuneko neurotransmisio dopaminergikoa lehengoratzen dute. Hala ere, tratamendu horiek sintomatikoak baino ez dira, denbora pasa ahala eraginkortasuna galtzen dute eta eragin kaltegarri larriak eragiten dituzte. Eragin kaltegarrietako batzuk administrazio bidearekin lotuta daude; izan ere, aho-bidezko farmakoek hartzaile dopaminergikoen aktibazio ez-jarraitua eragiten dute, tratamenduarekin lotutako asaldura motorren agerpena bultzatuz. Horregatik, tratamendu berritzaileak aurkitzeaz gain, segurtasun-profil hobeak dituzten administrazio-sistema berriak garatzea beharrezkoa da. Hala, azken urteetan nanopartikulen eraginkortasuna aztertzen duten ikerketa desberdinak burutu dira. Izan ere, nanopartikulek hesi hematoentzefalikoa (HHE) erraz zeharkatzeaz gain, farmakoen bioerabilgarritasuna eta eraginkortasuna hobetuz eragin kaltegarriak minimizatzen dituzte. Nanogarraiatzaile organiko eta ez-organiko desberdinak erabiliz, lebodopa, agonista dopaminergikoak edo faktore neurotrofikoak bezalako farmakoen eraginkortasuna aztertu da PG animalia-ereduetan, emaitza itxaropentsuak lortuz. Hala, nanoingeniaritzako partikulak oso tresna erabilgarria dirudite HHE gurutzatuz farmakoak modu seguru, eraginkor eta iraunkorrean emateko, eta beraz, PG bezalako nahasmendu neurologikoak tratatzeko etorkizun handiko estrategian bilaka daitezke.

Background In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function. Methods Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex. Results While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties. Conclusions Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.