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Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly co‐occur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low‐grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti‐diabetic agents have a decreased risk for the occurrence of AD and all‐cause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon‐like peptide 1 (GLP‐1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non‐insulin anti‐diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have T2DM. Many of the trials were conducted prior to the use of diagnostic biomarkers for AD. Trials have had a wide range of durations and population sizes. Many of the agents used to treat T2DM do not cross the blood brain barrier, and the effects are posited to occur via lowering of peripheral hyperglycaemia and reduction of peripheral and central inflammation. Clinical trials of anti‐diabetic agents to treat AD are ongoing and will provide insight into the therapeutic utility of these agents. [ABSTRACT FROM AUTHOR]

Affiliative tactile interactions buffer social mammals against neurobiological and behavioral effects of stress. The aim of this study was to investigate the cutaneous mechanisms underlying such beneficial consequences of touch by determining whether daily stroking, specifically targeted to activate a velocity/force tuned class of low‐threshold c‐fiber mechanoreceptor (CLTM), confers resilience against established markers of chronic unpredictable mild stress (CMS). Adult male Sprague Dawley rats were exposed to 2 weeks of CMS. Throughout the CMS protocol, some rats were stroked daily, either at CLTM optimal velocity (5 cm/s) or outside the CLTM optimal range (30 cm/s). A third CMS exposed group did not receive any tactile stimulation. The effect of CMS on serum corticosterone levels, anxiety‐ and depressive‐like behaviors in these three groups was assessed in comparison to a control group of non‐CMS exposed rats. While stroking did not mitigate the effects of CMS on body weight gain, CLTM optimal velocity stroking did significantly reduce CMS‐induced elevations in corticosterone following an acute forced‐swim. Rats receiving CLTM optimal stroking also showed significantly fewer anxiety‐like behaviors (elevated plus‐maze) than the other CMS exposed rats. In terms of depressive‐like behavior, whereas the same velocity‐specific resilience was observed in a forced‐swim test and social interaction test both groups of stroked rats spent significantly less time interacting than control rats, though they also spent significantly less time in the corner than non‐stroked CMS rats. Together, these findings support the theory CLTMs play a functional role in regulating the physiological condition of the body. [ABSTRACT FROM AUTHOR]

Cannabis contains a plethora of phytochemical constituents with diverse neurobiological effects. Cannabidiol (CBD) is the main non‐psychotropic component found in cannabis that is capable of modulating mesocorticolimbic DA transmission and may possess therapeutic potential for several neuropsychiatric disorders. Emerging evidence also suggests that, similar to CBD, omega‐3 polyunsaturated fatty acids may regulate DA transmission and possess therapeutic potential for similar neuropsychiatric disorders. Although progress has been made to elucidate the mechanisms underlying the therapeutic properties of CBD and omega‐3s, it remains unclear through which receptor mechanisms they may produce their purported effects. Peroxisome proliferator‐activated receptors are a group of nuclear transcription factors with multiple isoforms. PPARγ is an isoform activated by both CBD and omega‐3, whereas the PPARα isoform is activated by omega‐3. Interestingly, the activation of PPARγ and PPARα with selective agonists has been shown to decrease mesocorticolimbic DA activity and block neuropsychiatric symptoms similar to CBD and omega‐3s, raising the possibility that CBD and omega‐3s produce their effects through PPAR signaling. This review will examine the relationship between CBD, omega‐3s, and PPARs and how they may be implicated in the modulation of mesocorticolimbic DAergic abnormalities and associated neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Sedentary behaviors, such as computer use and sedentary video games, are barriers to physical activity, contribute to overweight and obesity among adolescents, and can adversely affect eating behaviors. Active video games may increase daily physical activity levels among adolescents and improve food‐related inhibitory control. We compared the effects of acute bouts of active and sedentary video gaming on event‐related potential (ERP) indices of food‐related inhibitory control, energy expenditure, and ad libitum eating. In a within‐subjects design, 59 adolescent participants (49% female, Mage = 13.29 ± 1.15) completed two separate counterbalanced, 60‐min long video gaming sessions separated by seven days. Immediately after, participants completed two go/no‐go tasks with high‐ and low‐calorie images and N2 and P3 ERP amplitudes were measured. Participants also completed a Stroop task and were given high‐ and low‐calorie snacks to consume ad libitum. Results indicated that active relative to sedentary video games significantly increased energy expenditure on multiple measures (e.g., METs, heart rate, kcals burned) and participants consumed more calories after the active compared to the sedentary video game session. N2 amplitudes were larger when participants inhibited to high‐ compared to low‐calorie foods, suggesting that high‐calorie foods necessitate increased the recruitment of inhibitory control resources; however, there were non‐significant differences for the N2 or P3 amplitudes, accuracy or response times, and Stroop performance between active versus sedentary video game sessions. Overall, sixty minutes of active video gaming increased energy expenditure and food consumption but did not significantly alter neural or behavioral measures of inhibitory control to food stimuli. [ABSTRACT FROM AUTHOR]

The reduced ability of central axons to regenerate after injury is significantly influenced by the presence of several molecules that inhibit axonal growth. Nogo-A is one of the most studied and most potent of the myelin-associated growth inhibitory molecules. Its neutralization, as well as interference with its signalling, allows for enhanced axonal sprouting and growth following injury. Using differentiated rat organotypic hippocampal slice cultures treated for 5 days with either of two different function-blocking anti-Nogo-A antibodies, we show an increase in CA3 fibre regeneration after lesion. In intact slices, 5 days of anti-Nogo-A antibody treatment led to increased sprouting of intact CA3 fibres that are positive for neurofilament 68. A transcriptomic approach confirmed the occurrence of a growth response on the molecular level upon Nogo-A neutralization in intact cultures. Our results demonstrate that Nogo-A neutralization for 5 days is sufficient for the induction of growth in mature CNS tissue without the prerequisite of an injury. Nogo-A may therefore act as a tonic growth suppressor/stabilizer in the adult intact hippocampus. [ABSTRACT FROM AUTHOR]

Infections are among the leading causes of death in spinal cord-injured patients, and are associated with hampered wound healing, prolonged hospitalization and impaired neurological recovery. We have analysed fluctuations of immune cell populations in an experimental rat model of spinal cord injury (SCI) by FACS analysis compared with sham-operated controls to detect the responses specifically induced by SCI. Further, to illustrate the impact of SCI only animals did not receive methylprednisolone in order to exclude confounding iatrogenic factors. Experimental SCI of rats induced a depletion of ED9+ monocytes (< 45%, P < 0.01), CD3+ T-lymphocytes (< 35%, P < 0.01), CD45 RA+ B-lymphocytes (< 25%, P < 0.01), MHC class II+ (< 40%, P < 0.01) and OX-62+ dendritic cells (< 50%, P = 0.032) within the first week after SCI. HIS 48+ granulocytes remained on levels similar to sham-operated controls. Our data suggest that experimental SCI induces early onset of an immune suppression that we refer to as SCI-immune depression syndrome. Iatrogenic application of methylprednisolone in patients suffering may worsen the immune suppression. A deeper understanding of the underlying mechanisms of this novel syndrome might be essential to decrease mortality, costs (time of hospitalization) and to protect the intrinsic neurological recovery potential following SCI. [ABSTRACT FROM AUTHOR]

The characteristic locomotor disturbances of Parkinson's disease (PD) include shuffling gait, short steps and low walking velocity. In this study we investigated features of walking and turning in a rat model of PD caused by unilateral infusion of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed gait and electromyographic (EMG) patterns of the ankle flexor tibialis anterior and the knee extensor vastus lateralis of the hindlimb, and triceps brachii of the forelimb, during overgound locomotion, spontaneous rotation (turning) and apomorphine-induced rotation. When compared with control rats, rats with unilateral dopamine depletion displayed a shuffling gait and short stride lengths. This locomotor pattern was accompanied by prolonged ankle flexor activity on the ipsilateral side, and prolonged activity of knee extensors on the contralateral side. The dopamine depletion also led to enhanced contraversive rotations after an apomorphine challenge. The EMG recordings during drug-induced rotation suggested that hindlimb stepping was a reflective response to an active drive produced by forelimbs. The EMG recordings of the contralateral side during rotation were marked by reduced ankle flexor activity and increased knee extensor activity. Furthermore, EMG recordings indicated that dopamine-agonists induce rotational bias by altering the coupling between ipsi- and contralateral hindlimbs, and between forelimbs. In straight walking, however, the gait of 6-OHDA lesion animals reflected normal, coupled hindlimb stepping as controlled by spinal pattern generators. The data suggest that the unilateral rat model of PD resembles key features of human parkinsonian gait, and that asymmetric descending input may underlie the observed changes in gait patterns. [ABSTRACT FROM AUTHOR]

The repulsive guidance molecule (RGM) is involved in the formation of the central nervous system (CNS) during development by modulating guidance of growing axons. However, a role of RGM in CNS injury remains to be established. We studied the expression of RGM in the spinal cord of rats with spinal cord injury (SCI). After SCI, RGM+ cells accumulated in lesions and peri-lesional areas. During the first days after SCI, RGM expression was confined to neurons, ballooned neurite fibers/retraction bulbs, smooth muscle/endothelial cells, and to leucocytes infiltrating the lesion. Lesional RGM expression was frequently confined to hypertrophicβ-APP+ and RhoA+ neurites/retraction bulbs. With maturation of the lesion, we observed RGM expression by components of the developing scar tissue (cicatrix), such as fibroblastoid cells, reactive astrocytes and in addition a pronounced extracellular RGM deposition resembling neo-laminae. Frequent RGM+, RhoA+ coexpression by lesional retraction bulbs represent first preliminary evidence of RGM to exert growth inhibitory effects by the second messenger system RhoA. To date, RGM is one of the most potent axonal growth inhibitors identified and present in axonal growth impediments (i) oligodendrocytes; (ii) the plexus choroideus and (iii) components of the developing scar. [ABSTRACT FROM AUTHOR]

It is believed that a major reason for the poor functional recovery after peripheral nerve lesion is collateral branching and regrowth of axons to incorrect muscles. Using a facial nerve injury protocol in rats, we previously identified a novel and clinically feasible approach to combat axonal misguidance– the application of neutralizing antibodies against neurotrophic factors to the injured nerve. Here, we investigated whether reduced collateral branching at the lesion site leads to better functional recovery. Treatment of rats with antibodies against nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor, insulin-like neurotrophic factor I, ciliary neurotrophic factor or glial cell line-derived neurotrophic factor increased the precision of reinnervation, as evaluated by multiple retrograde labelling of motoneurons, more than two-fold as compared with control animals. However, biometric analysis of vibrissae movements did not show positive effects on functional recovery, suggesting that polyneuronal reinnervation– rather than collateral branching– may be the critical limiting factor. In support of this hypothesis, we found that motor end-plates with morphological signs of multiple innervation were much more frequent in reinnervated muscles of rats that did not recover after injury (51% of all end-plates) than in animals with good functional performance (10%). Because polyneuronal innervation of muscle fibres is activity-dependent and can be manipulated, the present findings raise hopes that clinically feasible and effective therapies could be soon designed and tested. [ABSTRACT FROM AUTHOR]

Neutralizing the myelin-associated growth inhibitor Nogo-A in adult spinal cord-injured rats can promote regeneration of injured and compensatory sprouting of uninjured axons. Nogo-A is present in humans, making its neutralization a possible novel treatment option for paraplegic patients. In this study we examined the effects of an extensively used anti-Nogo-A antibody (mAb IN-1) on the regenerative capabilities of lesioned corticospinal tract (CST) axons in a primate, the Marmoset monkey. Unilateral thoracic lesions of the CST were performed in six adult Marmosets, followed by the application of mAb IN-1 into the cerebrospinal fluid circulation by a graft of hybridoma cells. A unilateral injection of biotin dextran amine into the motor cortex was performed to analyse sprouting and regeneration of the lesioned axons. In the control antibody-treated animal CST fibers stopped rostral to the lesion site and often showed retraction bulbs. In contrast, in four out of five mAb IN-1-treated animals fine labeled neurites had grown into, through and around the lesion site. Thus, this study provides first anatomical evidence that in primates, the neutralization of the myelin-associated inhibitor Nogo-A results in increased regenerative sprouting and growth of lesioned spinal cord axons. [ABSTRACT FROM AUTHOR]

Abstract This investigation was designed to study the spontaneous functional recovery of adult rats with incomplete spinal cord injury (SCI) at thoracic level during a time course of 2 weeks. Daily testing sessions included open field locomotor examination and electromyographic (EMG) recordings from a knee extensor (vastus lateralis, VL) and an ankle flexor muscle (tibialis anterior, TA) in the hindlimbs of treadmill walking rats. The BBB score (a locomotor score named after Basso et al. , 1995, J. Neurotrauma , 12 , 1–21) and various measures from EMG recordings were analysed (i.e. step cycle duration, rhythmicity of limb movements, flexor and extensor burst duration, EMG amplitude, root-mean-square, activity overlap between flexor and extensor muscles and hindlimb coupling). Directly after SCI, a marked drop in locomotor ability occurred in all rats with subsequent partial recovery over 14 days. The recovery was most pronounced during the first week. Significant changes were noted in the recovery of almost all analysed EMG measures. Within the 14 days of recovery, many of these measures approached control levels. Persistent abnormalities included a prolonged flexor burst and increased activity overlap between flexor and extensor muscles. Activity overlap between flexor and extensor muscles might be directly caused by altered descending input or by maladaptation of central pattern generating networks and/or sensory feedback. [ABSTRACT FROM AUTHOR]

Abstract Dystrophin and its autosomal homologue utrophin are coexpressed in muscle cells, and utrophin is functionally able to replace dystrophin in models of Duchenne muscular dystrophy. In brain, the two proteins are expressed differentially, suggesting distinct functional roles. Dystrophin is associated with postsynaptic GABAA receptors in hippocampus, cortex and cerebellum, whereas utrophin is present extrasynaptically, notably in large brainstem neurons. Here, the regulation of dystrophin and utrophin was investigated in a model of temporal lobe epilepsy. Adult mice were injected unilaterally with kainic acid into the dorsal hippocampus to induce loss of pyramidal cells and hypertrophy of dentate gyrus (DG) granule cells, as described (Neuroscience, 64, 665–674.). These morphological changes were associated with an increase in postsynaptic GABAA-receptors in the ipsilateral DG, as demonstrated by a parallel increase in punctate immunoreactivity to GABAA-receptor α2 subunit, gephyrin and dystrophin in the molecular layer. Thus, both dystrophin and gephyrin were involved in postsynaptic clustering of GABAA receptors. A transient induction of utrophin was seen at the onset of degeneration in CA1 and CA3 pyramidal cells and in the hilus. Most strikingly, however, utrophin immunoreactivity appeared in the granule cell layer of the DG and became very strong in hypertrophic granule cells 1–2 months post-kainate treatment. These results suggest that utrophin provides structural support of neuronal membranes, whereas dystrophin is a component of GABAergic synapses. [ABSTRACT FROM AUTHOR]

AbstractSlices from rat hippocampus in organotypic culture were used to study the biosynthesis regulation of chromogranins A and B and secretogranin II. Additionally, we investigated the proteolytic conversion of secretogranin II and the levels of prohormone convertases putatively involved. Forskolin treatment and depolarization with potassium plus BayK 8644 led to significant increases in secretogranin II mRNA in the principal cells of the hippocampus. Enhanced expression of secretogranin II was also reflected by a rise in peptide levels. Despite this induction of biosynthesis the extensive processing to secretoneurin normally observed in brain was maintained. Both forskolin and depolarization upregulated the prohormone convertase (PC)1, but not PC2, indicating that PC1 levels are critical for secretoneurin production under stimulating conditions. Results obtained for chromogranins A and B were less consistent. For chromogranin A mRNA, changes were restricted to granule cells; for chromogranin B, a response in granule cells was observed to depolarization but not to forskolin, and effects in pyramidal neurons were weak. Accordingly, we were unable to detect alterations in chromogranin A and B protein levels. Furthermore, we tested several neurotrophic growth factors and found that only basic fibroblast growth factor raised secretogranin II expression without affecting chromogranins A and B. The hippocampal slice preparation allowed well controlled treatment with identification of neuronal subpopulations and yielded data largely matching experiments in vivo and in cell culture. The pronounced regulation of secretogranin II and its effective processing underlines the importance of the resulting peptide secretoneurin as an active neuropeptide in the nervous system. [ABSTRACT FROM AUTHOR]

Abstract The chromogranin family comprises chromogranin A and B, and secretogranin II. The present study has focused on the axonal transport of chromogranins/secretogranin II and their detailed distribution in peripheral nerves and the spinal cord. With radioimmunoassay (RIA) and column chromatography, we first studied the processing of chromogranin B and secretogranin II during axonal transport. No larger precursors of these peptides were detected in the sciatic nerves, indicating that they are already processed to a high degree early during axonal transport. We also analysed nerve segments above and below a crush, using RIA, in order to compare these accumulation data with those obtained by the cytofluorimetric-scanning (CFS) technique. For the latter technique, the amounts of accumulation distal to the crush (presumably representing recycling and retrogradely transported peptides) were 30–40% of the amounts in the proximal accumulation for chromogranin A and secretoneurin, in contrast to chromogranin B, which showed 15% recycling. With the RIA, the corresponding values for secretoneurin and PE-11 (antibody against chromogranin B) were 42% and 14%, respectively. Therefore, the data obtained by CFS were in excellent agreement with those obtained by RIA. In crushed sciatic nerves, chromogranin A was present in large axons as well as in small- and medium-sized axons. Chromogranin B was mainly restricted to large axons, while secretoneurin was localized to bundles of small axons. This differential distribution was also found in the spinal roots and in the peripheral terminals. Chromogranin A was present in both ventral and dorsal roots, and chromogranin B was detected in ventral roots and in large sensory axons in the dorsal roots. Secretoneurin was dominant in the dorsal root. Double-labelling studies with antibodies against choline acetyltransferase/vesicular acetylcholine transporter, or against tyrosine hydroxylase, confirmed that chromogranin A was distributed in cholinergic, sensory, as well as adrenergic neurons. Chromogranin B was mainly present in cholinergic motor neurons and large sensory neurons, and secretoneurin was restricted to adrenergic and sensory neurons. The present study demonstrates that chromogranins A and B, and secretoneurin are transported with fast axonal transport in the peripheral nerves, with different amounts of recycling, and that they are differentially distributed in different types of neurons in the peripheral nervous system and the spinal cord, suggesting that each of them may play a special role in subsets of neurons. [ABSTRACT FROM AUTHOR]