Experience-Dependent Modulation of C. elegans Behavior by Ambient Oxygen

SummaryBackground: Ambient oxygen (O2) influences the behavior of organisms from bacteria to man. In C. elegans, an atypical O2 binding soluble guanylate cyclase (sGC), GCY-35, regulates O2 responses. However, how acute and chronic changes in O2 modify behavior is poorly understood.Results: Aggregating C. elegans strains can respond to a reduction in ambient O2 by a rapid, reversible, and graded inhibition of roaming behavior. This aerokinetic response is mediated by GCY-35 and GCY-36 sGCs, which appear to become activated as O2 levels drop and to depolarize the AQR, PQR, and URX neurons. Coexpression of GCY-35 and GCY-36 is sufficient to transform olfactory neurons into O2 sensors. Natural variation at the npr-1 neuropeptide receptor alters both food-sensing and O2-sensing circuits to reconfigure the salient features of the C. elegans environment. When cultivated in 1% O2 for a few hours, C. elegans reset their preferred ambient O2, seeking instead of avoiding 0%–5% O2. This plasticity involves reprogramming the AQR, PQR, and URX neurons.Conclusions: To navigate O2 gradients, C. elegans can modulate turning rates and speed of movement. Aerotaxis can be reprogrammed by experience or engineered artificially. We propose a model in which prolonged activation of the AQR, PQR, and URX neurons by low O2 switches on previously inactive O2 sensors. This enables aerotaxis to low O2 environments and may encode a “memory” of previous cultivation in low O2

Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae

Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and asso- ciated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment

Loss of CB1 receptors leads to differential age-related changes in reward-driven learning and memory

Previous studies have shown that cannabinoid 1 (CB1) receptor signaling dissociates between reward-associated and aversive memories. The influence of CB1 receptors on the aversion-driven spatial learning in the Morris water maze test is strongly age-dependent: mice with genetic deletion of CB1 receptors (Cnr1(−/−)) show superior learning when young but inferior learning when old compared to age-matched wild-type mice. Whether the reward-driven spatial learning is influenced in the same way by CB1 receptor signaling as the aversion-driven learning remains unclear. Thus, we examined the performance of Cn1(−/−) and their wild-type littermates at ages of 2-, 5-, and 12-months-old in the eight-arm radial maze test—a reward-motivated model of spatial learning. Interestingly, 2-months-old Cnr1(−/−) mice had a superior learning ability to wild-type mice. At the age of 5-months, Cnr1(−/−) mice showed the same performance as the wild-type littermates. However, 12-months-old Cnr1(−/−) mice showed significantly impaired performances in each parameter of the test. Accordingly, this study provides compelling support for our previous result that genetic deletion of CB1 receptor leads to early onset of age-related memory decline, similarly affecting both reward and aversion-driven learning

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes

Abstract Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain

Cannabinoid 1 receptor signaling on GABAergic neurons influences astrocytes in the ageing brain.

Astrocytes, key regulators of brain homeostasis, interact with neighboring glial cells, neurons and the vasculature through complex processes involving different signaling pathways. It is not entirely clear how these interactions change in the ageing brain and which factors influence astrocyte ageing. Here, we investigate the role of endocannabinoid signaling, because it is an important modulator of neuron and astrocyte functions, as well as brain ageing. We demonstrate that mice with a specific deletion of CB1 receptors on GABAergic neurons (GABA-Cnr1-/- mice), which show a phenotype of accelerated brain ageing, affects age-related changes in the morphology of astrocytes in the hippocampus. Thus, GABA-Cnr1-/- mice showed a much more pronounced age-related and layer-specific increase in GFAP-positive areas in the hippocampus compared to wild-type animals. The number of astrocytes, in contrast, was similar between the two genotypes. Astrocytes in the hippocampus of old GABA-Cnr1-/- mice also showed a different morphology with enhanced GFAP-positive process branching and a less polarized intrahippocampal distribution. Furthermore, astrocytic TNFα levels were higher in GABA-Cnr1-/- mice, indicating that these morphological changes were accompanied by a more pro-inflammatory function. These findings demonstrate that the disruption of endocannabinoid signaling on GABAergic neurons is accompanied by functional changes in astrocyte activity, which are relevant to brain ageing

Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus

Early onset of age-related changes in the brain of cannabinoid 1 receptor knockout (Cnr1−/−) mice suggests that cannabinoid 1 (CB1) receptor activity significantly influences the progression of brain aging. In the present study we show that lack of CB1 receptors leads to a significant increase in lipofuscin accumulation and a reduced expression and activity of cathepsin D, lysosomal protease implicated in the degradation of damaged macromolecules, in the hippocampus of 12-month-old mice. The impaired clearance of damaged macromolecules due to the low cathepsin D levels and not enhanced oxidative stress may be responsible for the lipofuscin accumulation because macromolecule oxidation levels were comparable between the genotypes within the same age group. The altered levels of autophagy markers p62 and LC3-II suggest that autophagy is upregulated in CB1 knockout mice. Increased autophagic

Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration

One of the two common hallmark lesions of Alzheimer’s disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE

Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior.

NMDA receptors are activated after binding of the agonist glutamate to the NR2 subunit along with a co-agonist, either L-glycine or D-serine, to the NR1 subunit. There is substantial evidence to suggest that D-serine is the most relevant co-agonist in forebrain regions and that alterations in D-serine levels contribute to psychiatric disorders. D-serine is produced through isomerization of L-serine by serine racemase (Srr), either in neurons or in astrocytes. It is released by astrocytes by an activity-dependent mechanism involving secretory vesicles. In the present study we generated transgenic mice (SrrTg) expressing serine racemase under a human GFAP promoter. These mice were biochemically and behaviorally analyzed using paradigms of anxiety, depression and cognition. Furthermore, we investigated the behavioral effects of long-term administration of D-serine added to the drinking water. Elevated brain D-serine levels in SrrTg mice resulted in specific behavioral phenotypes in the forced swim, novelty suppression of feeding and olfactory bulbectomy paradigms that are indicative of a reduced proneness towards depression-related behavior. Chronic dietary D-serine supplement mimics the depression-related behavioral phenotype observed in SrrTg mice. Our results suggest that D-serine supplementation may improve mood disorders