Sleep medicines are often prescribed for older adults (≥75 years) without appropriate dosing instructions: A nationwide retrospective register study in Finland.

BACKGROUND: Sleep medicines should be prescribed cautiously, accompanied by instructions that ensure appropriate use and reduce risks. This is especially important for older adults, for whom many of these medicines are classified as potentially inappropriate medicines. METHODS: We investigated the use and appropriateness of dosing instructions for sleep medicines (described in the Finnish National Current Care Guideline for Insomnia) prescribed for older adults (≥75 years) and dispensed with instruction label in pharmacies. The retrospective reimbursement register data for year 2020 by the Social Insurance Institution of Finland was used as the data source (1,080,843 purchases by 143,886 individuals of which 565,228 purchases were pharmacy dispenses). The appropriateness of the pharmacy dosing instructions containing keyword(s) referring to insomnia treatment was examined according to the prescribed dose, time of intake, frequency of use, and warnings/remarks. A random sample of 1000 instructions was used to manually analyze the phrasing and appropriateness. OUTCOMES: We focused our analysis on 58.1% (328,285 purchases by 87,396 individuals) of the pharmacy dispenses, which contained dosing instructions referring insomnia treatment. Of these, zopiclone and mirtazapine were the most prescribed drugs (134,631 and 112,463 purchases, respectively). Dose and time of intake were specified in most of the instructions (98.4% and 83.4%, respectively), whereas frequency of use was specified in 57.3%. A small percentage of the instructions included warnings/remarks (2.8%). Overall, only 2.1% of the instructions contained information about a single dose, time of intake, temporary use, and warnings/remarks and were thus defined as sufficient. Notably, 47.7% (n = 515,615) of all the purchases in our dataset were dispensed via automated multi-dose dispensing systems, which is aimed for long-term treatment. INTERPRETATION: It is common to prescribe sleep medicines for older adults without appropriate dosing instructions, particularly excluding warnings against long-term, regular use. Actions to change the current prescribing practices are warranted.

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects.

Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. SIGNIFICANCE STATEMENT: Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as N-methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.

TrkB neurotrophin receptor at the core of antidepressant effects, but how?

The role of brain-derived neurotrophic factor (BDNF) and its receptor TrkB has been studied in the context of mood disorders and their treatments for a couple of decades. Pharmacologically diverse antidepressant drugs increase the synthesis of BDNF in the cortex (and some subcortical structures) and this effect accounts for their ability to facilitate neurotrophic processes eventually leading into heightened plasticity within the cortex. Induction of BDNF-TrkB signaling has also been associated with the mechanism of action of ketamine and more recently with some other anesthetics, even with ones not thought to possess antidepressant potential. Notably, both ketamine and conventional antidepressants activate TrkB receptor and its downstream signaling rapidly within the same time scale in the brain while electroconvulsive therapy (ECT), among the most potent inducers of BDNF, has not been unequivocally shown to produce such acute effects on TrkB. The ability of antidepressants to regulate TrkB signaling is developmentally regulated and requires an intact central nervous system. The purpose of this review is to highlight and discuss some of these peculiarities associated with the effects of ketamine and classical antidepressants and BDNF on TrkB signaling.

Dyskinesia and brain-derived neurotrophic factor levels after long-term levodopa and nicotinic receptor agonist treatments in female mice with near-total unilateral dopaminergic denervation.

BACKGROUND: The treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role. Here, female mice with near-total unilateral 6-hydroxydopamine-induced nigrostriatal lesions were chronically treated with levodopa, and the effects of the α7 nicotinic receptor partial agonist AZD0328 and nicotine on LID were assessed. At the end of the experiment, BDNF protein levels in the prefrontal cortex and striatum were measured. RESULTS: Five-day treatments with three escalating doses of AZD0328 and a 10-week treatment with nicotine failed to alleviate LID. BDNF levels in the lesioned striatum correlated positively with LID severity, but no evidence was found for a levodopa-induced elevation of corticostriatal BDNF in the lesioned hemisphere. The nicotine treatment decreased BDNF levels in the prefrontal cortex but had no effect on striatal BDNF. CONCLUSIONS: The findings suggest that treatment of LID with nicotinic agonists may lose its effectiveness as the disease progresses, represent further evidence for a role for BDNF in LID, and expand previous knowledge on the effects of long-term nicotine treatment on BDNF.

Brief isoflurane anesthesia regulates striatal AKT-GSK3ß signaling and ameliorates motor deficits in a rat model of early-stage Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3ß (GSK3ß) and neurodegene-rative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3ß inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3ß within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3ß signaling in naïve rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3ß at the inhibitory Ser9 residue, and induced phosphorylation of AKTThr308 (protein kinase B; negative regulator of GSK3ß) in the striatum of naïve rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.

Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits.

Brain-derived neurotrophic factor (BDNF) plays pivotal roles in neuronal function. The cleaved - mature - form of BDNF (mBDNF), predominantly expressed in adult brains, critically determines its effects. However, insufficient proteolytic processing under pathology may lead to the precursor form of BDNF (proBDNF) and thereby increased neuronal apoptosis and synaptic weakening. Previous findings in our lab showed that cognitive stimulation (CS) delayed memory decline in Tg2576 mouse model of Alzheimer's disease (AD), an effect that was tightly associated with augmented levels of mBDNF. In view of this association, the present study explored whether altered cleavage of BDNF could be involved in AD-related traits triggered by excessive amyloid-ß (Aß) pathology and whether this process could be therapeutically targeted. Aß pathology, both in AD patient samples and experimental models, triggered the upregulation of plasminogen-activator inhibitor-1 (PAI-1) via JNK/c-Jun. This led to inhibition of plasmin-regulated conversion of mBDNF. Pharmacological inhibition of PAI-1 with PAI-039 sufficiently reverted Aß-induced tau hyperphosphorylation and neurotoxicity. Chronic treatment of 15 old-month Tg2576 mice with oral administration of PAI-039 resulted in improved BDNF maturation and cognitive function without inducing significant changes in amyloid burden. In conclusion, upregulation of PAI-1 may be a critical mechanism underlying insufficient neurotrophic support and increased neurodegeneration associated with AD. Thus, targeting BDNF maturation through pharmacological inhibition of PAI-1 might become a potential treatment for AD.

Combined ipsilateral limb use score as an index of motor deficits and neurorestoration in parkinsonian rats.

Our aim was to apply a robust non-drug induced sensorimotor test battery to assess the efficacy of neurorestorative therapies on the motor deficits caused by partial unilateral 6-OHDA lesion mimicking early stage PD. Since the 6-OHDA lesion protocols to induce partial DA depletion in striatum vary extensively between laboratories, we evaluated the associations between different intrastriatal 6-OHDA doses (1 X 0-20 and 2 X 0-30 µg), striatal DA depletion (HPLC-ECD) and D-amphetamine induced rotation to identify a lesion protocol that would produce 40-60% striatal DA depletion. Doses ≥ 6 µg produced a significant DA depletion (ANOVA, P < 0.0001). 6-OHDA dose range (6-14 µg) causing 40-60% DA depletion induced very variable rotational responses. Next, intrastriatal 1 × 10 and 1 × 14 µg doses were compared with a full lesion (10 µg into the medial forebrain bundle) with regard to their effects on adjusting step, cylinder, and vibrissae test performance. A combined ipsilateral score (average of each test) was found more sensitive in distinguishing between different lesions than any test alone. Finally, five-week treadmill exercise starting two weeks post-lesion was able to restore impaired limb use (combined score; mixed model, P < 0.05) and striatal DA depletion (ANOVA, P < 0.05) in rats with partial lesion (1 × 10 µg). Notably, D-amphetamine induced rotation significantly decreased between weeks one to seven post-lesion (t-test, P < 0.01). In conclusion, intrastriatal 1 × 10 µg of 6-OHDA produces 40-60% striatal DA depletion robustly, and the combined ipsilateral score provides an efficient means for testing of the efficacy of neurorestorative or neuroprotective treatments for PD. © 2017 Wiley Periodicals, Inc.

Nimodipine activates TrkB neurotrophin receptors and induces neuroplastic and neuroprotective signaling events in the mouse hippocampus and prefrontal cortex.

The L-type calcium channel blocker nimodipine improves clinical outcome produced by delayed cortical ischemia or vasospasm associated with subarachnoid hemorrhage. While vasoactive mechanisms are strongly implicated in these therapeutic actions of nimodipine, we sought to test whether nimodipine might also regulate neurotrophic and neuroplastic signaling events associated with TrkB neurotrophin receptor activation. Adult male mice were acutely treated with vehicle or nimodipine (10 mg/kg, s.c., 1.5 h) after which the phosphorylation states of TrkB, cyclic-AMP response element binding protein (CREB), protein kinase B (Akt), extracellular regulated kinase (ERK), mammalian target of rapamycin (mTor) and p70S6 kinase (p70S6k) from prefrontal cortex and hippocampus were assessed. Nimodipine increased the phosphorylation of the TrkB catalytic domain and the phosphoslipase-Cγ1 (PLCγ1) domain, whereas phosphorylation of the TrkB Shc binding site remained unaltered. Nimodipine-induced TrkB phosphorylation was associated with increased phosphorylation levels of Akt and CREB in the prefrontal cortex and the hippocampus whereas phosphorylation of ERK, mTor and p70S6k remained unaltered. Nimodipine-induced TrkB signaling was not associated with changes in BDNF mRNA or protein levels. These nimodipine-induced changes on TrkB signaling mimic those produced by antidepressant drugs and thus propose common mechanisms and long-term functional consequences for the effects of these medications. This work provides a strong basis for investigating the role of TrkB-associated signaling underlying the neuroprotective and neuroplastic effects of nimodipine in translationally relevant animal models of brain trauma or compromised synaptic plasticity.

Effects of nitrous oxide and ketamine on electrophysiological and molecular responses in the prefrontal cortex of mice: A comparative study.

Nitrous oxide (N2O; laughing gas) has recently reported to produce rapid antidepressant effects, but little is known about the underlying mechanisms. We performed transcriptomics, in situ hybridization, and electrophysiological studies to examine the potential shared signatures induced by 1 h inhalation of 50% N2O and a single subanesthetic dose of ketamine (10 mg/kg, i.p.) in the medial prefrontal cortex (mPFC) in adult mice. Both treatments similarly affected the transcription of several negative regulators of mitogen-activated protein kinases (MAPKs), namely, dual specificity phosphatases (DUSPs). The effects were primarily located in the pyramidal cells. Notably, the overall effects of N2O on mRNA expression were much more prominent and widespread compared to ketamine. Ketamine caused an elevation of the spiking frequency of putative pyramidal neurons and increased gamma activity (30-100 Hz) of cortical local field potentials. However, N2O produced no such effects. Spiking amplitudes and spike-to-local field potential phase locking of putative pyramidal neurons and interneurons in this brain area showed no uniform changes across treatments. Our findings suggest that N2O and subanesthetic-dose ketamine target MAPK pathway in the mPFC but produce varying acute electrophysiological responses.

Brain Plasticity Modulator p75 Neurotrophin Receptor in Human Urine after Different Acute Brain Injuries-A Prospective Cohort Study.

Acute brain injuries (ABIs) pose a substantial global burden, demanding effective prognostic indicators for outcomes. This study explores the potential of urinary p75 neurotrophin receptor (p75NTR) concentration as a prognostic biomarker, particularly in relation to unfavorable outcomes. The study involved 46 ABI patients, comprising sub-cohorts of aneurysmal subarachnoid hemorrhage, ischemic stroke, and traumatic brain injury. Furthermore, we had four healthy controls. Samples were systematically collected from patients treated at the University Hospital of Turku between 2017 and 2019, at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) post-admission time points. Urinary p75NTR levels, measured by ELISA and normalized to creatinine, were compared against patients' outcomes using the modified Rankin Scale (mRS). Early urine samples showed no significant p75NTR concentration difference between favorable and unfavorable mRS groups. In contrast, late samples exhibited a statistically significant increase in p75NTR concentrations in the unfavorable group (p = 0.033), demonstrating good prognostic accuracy (AUC = 70.9%, 95% CI = 53-89%, p = 0.03). Assessment of p75NTR concentration changes over time revealed no significant variation in the favorable group (p = 0.992) but a significant increase in the unfavorable group (p = 0.009). Moreover, p75NTR concentration was significantly higher in ABI patients (mean ± SD 40.49 ± 28.83-65.85 ± 35.04 ng/mg) compared to healthy controls (mean ± SD 0.54 ± 0.44 ng/mg), irrespective of sampling time or outcome (p < 0.0001). In conclusion, late urinary p75NTR concentrations emerged as a potential prognostic biomarker for ABIs, showing increased levels associated with unfavorable outcomes regardless of the specific type of brain injury. While early samples exhibited no significant differences, the observed late increases emphasize the time-dependent nature of this potential biomarker. Further validation in larger patient cohorts is crucial, highlighting the need for additional research to establish p75NTR as a reliable prognostic biomarker across various ABIs. Additionally, its potential role as a diagnostic biomarker warrants exploration.

Linking Hypothermia and Altered Metabolism with TrkB Activation.

Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3ß (GSK3ß). Increased TrkB, GSK3ß, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

SPECT/CT imaging reveals CNS-wide modulation of glymphatic cerebrospinal fluid flow by systemic hypertonic saline.

Intrathecal administration enables central nervous system delivery of drugs that do not bypass the blood-brain barrier. Systemic administration of hypertonic saline (HTS) enhances delivery of intrathecal therapeutics into the neuropil, but its effect on solute clearance from the brain remains unknown. Here, we developed a dynamic in vivo single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging platform to study the effects of HTS on whole-body distribution of the radiolabeled tracer 99mTc-diethylenetriaminepentaacetic acid (DTPA) administered through intracisternal, intrastriatal, or intravenous route in anesthetized rats. Co-administration of systemic HTS increased intracranial exposure to intracisternal 99mTc-DTPA by ∼80% during imaging. In contrast, HTS had minimal effects on brain clearance of intrastriatal 99mTc-DTPA. In sum, SPECT/CT imaging presents a valuable approach to study glymphatic drug delivery. Using this methodology, we show that systemic HTS increases intracranial availability of cerebrospinal fluid-administered tracer, but has marginal effects on brain clearance, thus substantiating a simple, yet effective strategy for enhancing intrathecal drug delivery to the brain.

BDNF and TrkB in neuronal differentiation of Fmr1-knockout mouse.

Fragile X syndrome (FXS) is a common cause of inherited mental retardation and the best characterized form of autistic spectrum disorders. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP), which leads to abnormalities in the differentiation of neural progenitor cells (NPCs) and in the development of dendritic spines and neuronal circuits. Brain-derived neurotrophic factor (BDNF) and its TrkB receptors play a central role in neuronal maturation and plasticity. We studied BDNF/TrkB actions in the absence of FMRP and show that an increase in catalytic TrkB expression in undifferentiated NPCs of Fmr1-knockout (KO) mice, a mouse model for FXS, is associated with changes in the differentiation and migration of neurons expressing TrkB in neurosphere cultures and in the developing cortex. Aberrant intracellular calcium responses to BDNF and ATP in subpopulations of differentiating NPCs combined with changes in the expression of BDNF and TrkB suggest cell subtype-specific alterations during early neuronal maturation in the absence of FMRP. Furthermore, we show that dendritic targeting of Bdnf mRNA was increased under basal conditions and further enhanced in cortical layer V and hippocampal CA1 neurons of Fmr1-KO mice by pilocarpine-induced neuronal activity represented by convulsive seizures, suggesting that BDNF/TrkB-mediated feedback mechanisms for strengthening the synapses were compromised in the absence of FMRP. Pilocarpine-induced seizures caused an accumulation of Bdnf mRNA transcripts in the most proximal segments of dendrites in cortical but not in hippocampal neurons of Fmr1-KO mice. In addition, BDNF protein levels were increased in the hippocampus but reduced in the cortex of Fmr1-KO mice in line with regional differences of synaptic plasticity in the brain of Fmr1-KO mice. Altogether, the present data suggest that alterations in the BDNF/TrkB signaling modulate brain development and impair synaptic plasticity in FXS.

Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia.

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2 O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.

Tianeptine induces expression of dual specificity phosphatases and evokes rebound emergence of cortical slow wave electrophysiological activity.

BACKGROUND: The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N2O) gradually evoke 1-4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3ß (GSK3ß)). METHODS: We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting. RESULTS: An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2-2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3ß remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) - negative regulators of MAPK. CONCLUSION: Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N2O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3ß signaling.

A wake-up call: Sleep physiology and related translational discrepancies in studies of rapid-acting antidepressants.

Depression is frequently associated with sleep problems, and clinical improvement often coincides with the normalization of sleep architecture and realignment of circadian rhythm. The effectiveness of treatments targeting sleep in depressed patients, such as sleep deprivation, further demonstrates the confluence of sleep and mood. Moreover, recent studies showing that the rapid-acting antidepressant ketamine influences processes related to sleep-wake neurobiology have led to novel hypotheses explaining rapid and sustained antidepressant effects. Despite the available evidence, studies addressing ketamine's antidepressant effects have focused on pharmacology and often overlooked the role of physiology. To explore this discrepancy in research on rapid-acting antidepressants, we examined articles published between 2009-2019. A keyword search algorithm indicated that vast majority of the articles completely ignored sleep. Out of the 100 most frequently cited preclinical and clinical research papers, 89 % and 71 %, respectively, did not mention sleep at all. Furthermore, only a handful of these articles disclosed key experimental variables, such as the times of treatment administration or behavioral testing, let alone considered the potential association between these variables and experimental observations. Notably, in preclinical studies, treatments were preferentially administered during the inactive period, which is the polar opposite of clinical practice and research. We discuss the potential impact of this practice on the results in the field. Our hope is that this perspective will serve as a wake-up call to (re)-examine rapid-acting antidepressant effects with more appreciation for the role of sleep and chronobiology.

Brain-derived neurotrophic factor controls activity-dependent maturation of CA1 synapses by downregulating tonic activation of presynaptic kainate receptors.

Immature hippocampal synapses express presynaptic kainate receptors (KARs), which tonically inhibit glutamate release. Presynaptic maturation involves activity-dependent downregulation of the tonic KAR activity and consequent increase in release probability; however, the molecular mechanisms underlying this developmental process are unknown. Here, we have investigated whether brain derived neurotrophic factor (BDNF), a secreted protein implicated in developmental plasticity in several areas of the brain, controls presynaptic maturation by regulating KARs. Application of BDNF in neonate hippocampal slices resulted in increase in synaptic transmission that fully occluded the immature-type KAR activity in area CA1. Conversely, genetic ablation of BDNF was associated with delayed synaptic maturation and persistent presynaptic KAR activity, suggesting a role for endogenous BDNF in the developmental regulation of KAR function. In addition, our data suggests a critical role for BDNF TrkB signaling in fast activity-dependent regulation of KARs. Selective acute inhibition of TrkB receptors using a chemical-genetic approach prevented rapid change in synapse dynamics and loss of tonic KAR activity that is typically seen in response to induction of LTP at immature synapses. Together, these data show that BDNF-TrkB-dependent maturation of glutamatergic synapses is tightly associated with a loss of endogenous KAR activity. The coordinated action of these two receptor mechanisms has immediate physiological relevance in controlling presynaptic efficacy and transmission dynamics at CA3-CA1 synapses at a stage of development when functional contact already exists but transmission is weak.

Regulation of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) by anti-parkinsonian drug therapy in vivo.

Available treatment for Parkinson's disease (PD) is mainly symptomatic instead of halting or reversing degenerative processes affecting the disease. Research on the molecular pathogenesis of PD has suggested reduced trophic support as a possible cause or mediator of neurodegeneration. In animal models of the disease, neurotrophic factors prevent neurodegeneration and induce behavioral recovery. Some anti-Parkinsonian drugs show neuroprotective activity, but it is not known whether the drug-induced neuroprotection is mediated by neurotrophic factors. In this study, we have investigated the influence of two neuroprotective anti-Parkinsonian drugs, the monoamine oxidase B inhibitor selegiline and the adenosine A(2A) antagonist SCH 58261, on the levels of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) in the mouse brain. Protein levels of BDNF and CDNF were quantified by western blot after 2 weeks of treatment with either of the drugs or placebo. CDNF levels were not significantly influenced by selegiline or SCH 58261 in any brain area studied. Selegiline treatment significantly increased BDNF levels in the anterior cingulate cortex (1.55 +/- 0.22, P < 0.05, Student's t-test). In the striatum, selegiline increased BDNF content by 32%, but this change did not reach statistical significance (1.32 +/- 0.15, P < 0.13, Student's t-test). Our data suggest that neurotrophic factors, particularly BDNF may play a role in the neuroprotective effects of selegiline, but do not support the hypothesis that anti-Parkinsonian drugs would work by increasing the levels of CDNF in brain.

Darkness reduces BDNF expression in the visual cortex and induces repressive chromatin remodeling at the BDNF gene in both hippocampus and visual cortex.

Neuronal activity regulates the expression of brain-derived neurotrophic factor (BDNF) in brain. In darkness, reduced neuronal activity in the visual cortex markedly decreases total BDNF transcription level in adult rats. Epigenetic mechanisms are crucially involved in the regulation of gene expression in response to environmental stimuli. In this study, we examined the effect of 1 week of light deprivation (LD) on the activity-dependent changes in BDNF expression from different promoters in the visual cortex and hippocampus. We analyzed the correlation between the chromatin state of Bdnf promoters, exon-specific transcripts levels, and total protein levels in light-deprived rats and in rats reared under normal light-dark cycle. We found that 1 week of LD significantly reduced Bdnf mRNA and protein in the visual cortex but not in the hippocampus. However, epigenetic analysis revealed that LD increased histone-3 methylation and DNA methylation at the Bdnf promoter IV in both the visual cortex and hippocampus. These data highlight the spatial differences in signaling pathways that lead to the BDNF expression in response to diminished ambient light.