Structural, Functional, and Genetic Changes Surrounding Electrodes Implanted in the Brain.

Implantable neurotechnology enables monitoring and stimulating of the brain signals responsible for performing cognitive, motor, and sensory tasks. Electrode arrays implanted in the brain are increasingly used in the clinic to treat a variety of sources of neurological diseases and injuries. However, the implantation of a foreign body typically initiates a tissue response characterized by physical disruption of vasculature and the neuropil as well as the initiation of inflammation and the induction of reactive glial states. Likewise, electrical stimulation can induce damage to the surrounding tissue depending on the intensity and waveform parameters of the applied stimulus. These phenomena, in turn, are likely influenced by the surface chemistry and characteristics of the materials employed, but further information is needed to effectively link the biological responses observed to specific aspects of device design. In order to inform improved design of implantable neurotechnology, we are investigating the basic science principles governing device-tissue integration. We are employing multiple techniques to characterize the structural, functional, and genetic changes that occur in the cells surrounding implanted electrodes. First, we have developed a new "device-in-slice" technique to capture chronically implanted electrodes within thick slices of live rat brain tissue for interrogation with single-cell electrophysiology and two-photon imaging techniques. Our data revealed several new observations of tissue remodeling surrounding devices: (a) there was significant disruption of dendritic arbors in neurons near implants, where losses were driven asymmetrically on the implant-facing side. (b) There was a significant loss of dendritic spine densities in neurons near implants, with a shift toward more immature (nonfunctional) morphologies. (c) There was a reduction in excitatory neurotransmission surrounding implants, as evidenced by a reduction in the frequency of excitatory postsynaptic currents (EPSCs). Lastly, (d) there were changes in the electrophysiological underpinnings of neuronal spiking regularity. In parallel, we initiated new studies to explore changes in gene expression surrounding devices through spatial transcriptomics, which we applied to both recording and stimulating arrays. We found that (a) device implantation is associated with the induction of hundreds of genes associated with neuroinflammation, glial reactivity, oligodendrocyte function, and cellular metabolism and (b) electrical stimulation induces gene expression associated with damage or plasticity in a manner dependent upon the intensity of the applied stimulus. We are currently developing computational analysis tools to distill biomarkers of device-tissue interactions from large transcriptomics data sets. These results improve the current understanding of the biological response to electrodes implanted in the brain while producing new biomarkers for benchmarking the effects of novel electrode designs on responses. As the next generation of neurotechnology is developed, it will be increasingly important to understand the influence of novel materials, surface chemistries, and implant architectures on device performance as well as the relationship with the induction of specific cellular signaling pathways.

Ultrafast Water H-Bond Rearrangement in a Metal-Organic Framework Probed by Femtosecond Time-Resolved Infrared Spectroscopy.

We investigated the water H-bond network and its dynamics in Ni2Cl2BTDD, a prototypical MOF for atmospheric water harvesting, using linear and ultrafast IR spectroscopy. Utilizing isotopic labeling and infrared spectroscopy, we found that water forms an extensive H-bonding network in Ni2Cl2BTDD. Further investigation with ultrafast spectroscopy revealed that water can reorient in a confined cone up to ∼50° within 1.3 ps. This large angle reorientation indicates H-bond rearrangement, similar to bulk water. Thus, although the water H-bond network is confined in Ni2Cl2BTDD, different from other confined systems, H-bond rearrangement is not hindered. The picosecond H-bond rearrangement in Ni2Cl2BTDD corroborates its reversibility with minimal hysteresis in water sorption.

The effects of sex, nation, ethnicity, age and self-reported pubertal development on participant-measured right-left 2D:4D (Dr-l) in the BBC internet study.

Digit ratio (2D:4D) - a proxy for prenatal sex steroids - shows sex, nationality and ethnic differences and is linked to pubertal onset. It is unclear whether right-left 2D:4D (Dr-l) also correlates with prenatal sex steroids, as evidence of these differences has been less conclusive. The present study examined the effects of sex, nation, ethnicity, age and self-reported pubertal development (i.e. the rate of physical development and age at menarche [females] or first shave [males]) on Dr-l in a large online study (the BBC internet study). Digit lengths were self-measured in 201,865 adults (110,955 males) and the sample of nations included 41 countries. Participants reported the self-perceived rate of physical pubertal development on a five-point scale (from very slow to very fast) and provided information on the age at menarche or first shave. Adult (>17 years) males had lower Dr-l than females with weak effect size across 41 nations (males-females; d = -.065, p < .0001). There were sex and ethnicity effects on Dr-l across seven ethnic groups with males < females and lower Dr-l in Whites and Middle/Near Eastern participants compared to Asian, Black and Chinese respondents. Considering age effects, the authors focused on participants >12 years; there were stable sex differences and a weak positive effect of age on Dr-l. Dr-l showed a positive relationship with the rate of physical development and a negative relationship with age at menarche or first shave. Relationships were present in males and females with stronger effects in the latter. It is concluded that Dr-l shows a weak sex difference (males < females) independent of nation, ethnicity and age, and suggest that Dr-l is a proxy for prenatal sex steroids.

Understanding Pedophilia: A Theoretical Framework on the Development of Sexual Penchants.

Pedophilia is a significant public health problem. Despite its cost to society, little effort has been directed toward understanding idiographic differences in the development and maintenance of pedophilia. Extant literature emphasizes biological underpinnings and predictors of re-offense. In this article, we posit that pedophilic penchants in males originate due to language, cognition, emotions, and emotion regulation. Adverse childhood experiences, such as emotional and sexual abuse, are posited as a major contributor to the etiology of pedophilia. However, not all individuals attracted to minors present with similar childhood adversities. The development of pedophilia, in the absence of such direct training (childhood adversities), is difficult to comprehend. Relational frame theory, a comprehensive account of human language and cognition, aids in deciphering the idiographic underpinnings of pedophilia. The role of maladaptive emotion regulation in maintaining pedophilia is also described. This article presents examples of how relational frames are established and activated in distressing contexts. Finally, implications for future research are discussed.

Preparation of nitriles from aldehydes using ammonium persulfate by means of a nitroxide-catalysed oxidative functionalisation reaction.

A methodology for the preparation of nitriles from aldehydes by means of an oxidative functionalisation reaction is reported. It employs ammonium persulfate as both the primary oxidant and the nitrogen source, and a catalytic amount of a nitroxide. It is applicable to a range of structurally diverse (hetero)aromatic aldehydes furnishing the nitrile products in 30-97% isolated yield. Given the ready accessibility of aldehydes and that ammonium persulfate is cheap and less toxic than many other reagents for generating nitriles, this methodology offers a simple and easy to use approach to this valuable class of compounds.

Parental income inequality and children's digit ratio (2D:4D): a 'Trivers-Willard' effect on prenatal androgenization?

Income inequality is associated positively with disease prevalence and mortality. Digit ratio (2D:4D) - a negative proxy for prenatal testosterone and a positive correlate of prenatal oestrogen - is related to several diseases. This study examined the association of income inequality (operationalized as relative parental income) and children's 2D:4D. Participants self-measured finger lengths (2D=index finger, and 4D=ring finger) in a large online survey conducted in July 2005 (the BBC Internet Study) and reported their parents' income. Children of parents of above-average income had low 2D:4D (high prenatal testosterone, low prenatal oestrogen) while the children of parents of below-average income had high 2D:4D (low prenatal testosterone, high prenatal oestrogen). The effects were significant in the total sample, present among Whites (the largest group in the sample), in the two largest national samples (UK and USA) and were greater for males than females. The findings suggest a Trivers-Willard effect, such that high-income women may prenatally masculinize their sons at the expense of the fitness of their daughters. Women with low income may prenatally feminize their daughters at the fitness expense of their sons. The effect could, in part, explain associations between low income, high 2D:4D (low prenatal testosterone) and some major causes of mortality such as cardiovascular disease.

Digit ratio (2D:4D) and body mass index in the BBC Internet Study: prenatal sex steroids and a Trivers-Willard effect on body composition.

Digit ratio - a putative measure of prenatal sex steroids - may be related to body mass index (BMI). However, reports of correlations between 2D:4D and BMI have yielded mixed results with some studies showing no relationship while others have reported positive associations in men or women only. This study considers associations between self-reported 2D:4D and BMI in a large online survey (i.e. the BBC Internet Study). At the individual level, there was a weak positive association between 2D:4D and BMI in both sexes with greater effect sizes in women. Body mass index was positively related to age and negatively related to parental income; however, the relationship between 2D:4D and BMI was independent of both variables. At the national level, mean 2D:4D per country showed positive associations with mean national BMI but those correlations were restricted to females. It is concluded that BMI is positively related to low prenatal testosterone and high prenatal oestrogen. Parental income inequality may influence both prenatal sex steroids (through a 'Trivers-Willard' effect) and BMI such that increases in inequality result in reductions in prenatal testosterone and increases in BMI at the individual and national level.

Associations of experiential avoidance with burnout, wellbeing, and productivity loss among police officers: The mediating role of negative and positive affect.

OBJECTIVES: The current study aims to investigate the indirect associations between experiential avoidance (EA) and burnout, wellbeing, and productivity loss (PL) via the mediating role of positive and negative emotions among police officers. METHODS: Data were collected on 187 officers (84% male) aged 21-64 years between 2019 and 2020. Participants completed online self-report measures. RESULTS: EA was indirectly associated with burnout via positive and negative affect. EA was indirectly associated with wellbeing through positive affect, positive affect and burnout, and negative affect and burnout. Finally, EA was indirectly associated with PL via positive affect and burnout, and negative affect and burnout. CONCLUSION: Results provide support for the role of EA in officers' wellbeing and job performance via increasing negative affect and decreasing positive affect. This highlights the importance of interventions, such as acceptance and commitment therapy that target acceptance and psychological flexibility.

Ultrafast Dynamics at Lipid-Water Interfaces.

Lipid membranes are more than just barriers between cell compartments; they provide molecular environments with a finely tuned balance between hydrophilic and hydrophobic interactions that enable proteins to dynamically fold and self-assemble to regulate biological function. Characterizing dynamics at the lipid-water interface is essential to understanding molecular complexities from the thermodynamics of liquid-liquid phase separation down to picosecond-scale reorganization of interfacial hydrogen-bond networks.Ultrafast vibrational spectroscopy, including two-dimensional infrared (2D IR) and vibrational sum-frequency generation (VSFG) spectroscopies, is a powerful tool to examine picosecond interfacial dynamics. Two-dimensional IR spectroscopy provides a bond-centered view of dynamics with subpicosecond time resolutions, as vibrational frequencies are highly sensitive to the local environment. Recently, 2D IR spectroscopy has been applied to carbonyl and phosphate vibrations intrinsically located at the lipid-water interface. Interface-specific VSFG spectroscopy probes the water vibrational modes directly, accessing H-bond strength and water organization at lipid headgroup positions. Signals in VSFG arise from the interfacial dipole contributions, directly probing headgroup ordering and water orientation to provide a structural view of the interface.In this Account we discuss novel applications of ultrafast spectroscopy to lipid membranes, a field that has experienced significant growth over the past decade. In particular, ultrafast experiments now offer a molecular perspective on increasingly complex membranes. The powerful combination of ultrafast, interface-selective spectroscopy and simulations opens up new routes to understanding multicomponent membranes and their function. This Account highlights key prevailing views that have emerged from recent experiments: (1) Water dynamics at the lipid-water interface are slow compared to those of bulk water as a result of disrupted H-bond networks near the headgroups. (2) Peptides, ions, osmolytes, and cosolvents perturb interfacial dynamics, indicating that dynamics at the interface are affected by bulk solvent dynamics and vice versa. (3) The interfacial environment is generally dictated by the headgroup structure and orientation, but hydrophobic interactions within the acyl chains also modulate interfacial dynamics. Ultrafast spectroscopy has been essential to characterizing the biophysical chemistry of the lipid-water interface; however, challenges remain in interpreting congested spectra as well as designing appropriate model systems to capture the complexity of a membrane environment.

The axis of the receptor for advanced glycation endproducts in asthma and allergic airway disease.

Asthma is a generalized term that describes a scope of distinct pathologic phenotypes of variable severity, which share a common complication of reversible airflow obstruction. Asthma is estimated to affect almost 400 million people worldwide, and nearly ten percent of asthmatics have what is considered "severe" disease. The majority of moderate to severe asthmatics present with a "type 2-high" (T2-hi) phenotypic signature, which pathologically is driven by the type 2 cytokines Interleukin-(IL)-4, IL-5, and IL-13. However, "type 2-low" (T2-lo) phenotypic signatures are often associated with more severe, steroid-refractory neutrophilic asthma. A wide range of clinical and experimental studies have found that the receptor for advanced glycation endproducts (RAGE) plays a significant role in the pathogenesis of asthma and allergic airway disease (AAD). Current experimental data indicates that RAGE is a critical mediator of the type 2 inflammatory reactions which drive the development of T2-hi AAD. However, clinical studies demonstrate that increased RAGE ligands and signaling strongly correlate with asthma severity, especially in severe neutrophilic asthma. This review presents an overview of the current understandings of RAGE in asthma pathogenesis, its role as a biomarker of disease, and future implications for mechanistic studies, and potential therapeutic intervention strategies.

Preparation of hexafluoroisopropyl esters by oxidative esterification of aldehydes using sodium persulfate.

A simple, metal-free route for the oxidative esterification of aldehydes to yield hexafluoroisopropyl esters is reported. The methodology employs sodium persulfate and a catalytic quantity of a nitroxide and is applicable to aromatic, heteroaromatic, and aliphatic aldehydes.

Potential microbial bioindicators of phosphorus mining in a temperate deciduous forest.

AIMS: The soil microbial community plays a critical role in increasing phosphorus (P) availability in low-P, weathered soils by "mining" recalcitrant organic P through the production of phosphatase enzymes. However, there is a lack of data on the fungal and bacterial taxa which are directly involved in P mining, which could also serve as potential microbial bioindicators of low P availability. METHODS AND RESULTS: Leveraging a 5-year P enrichment experiment on low-P forest soils, high-throughput sequencing was used to profile the microbial community to determine which taxa associate closely with P availability. We hypothesized that there would be a specialized group of soil micro-organisms that could access recalcitrant P and whose presence could serve as a bioindicator of P mining. Community profiling revealed several candidate bioindicators of P mining (Russulales, Acidobacteria Subgroup 2, Acidobacteriales, Obscuribacterales and Solibacterales), whose relative abundance declined with elevated P and had a significant, positive association with phosphatase production. In addition, we identified candidate bioindicators of high P availability (Mytilinidales, Sebacinales, Chitinophagales, Cytophagales, Saccharimonadales, Opitulales and Gemmatales). CONCLUSIONS: This research provides evidence that mitigating P limitation in this ecosystem may be a specialized trait and is mediated by a few microbial taxa. SIGNIFICANCE AND IMPACT OF THE STUDY: Here, we characterize Orders of soil microbes associated with manipulated phosphorus availability in forest soils to determine bioindicator candidates for phosphorus. Likewise, we provide evidence that the microbial trait to utilize recalcitrant organic forms of P (e.g. P mining) is likely a specialized trait and not common to all members of the soil microbial community. This work further elucidates the role that a complex microbial community plays in the cycling of P in low-P soils, and provides evidence for future studies on microbial linkages to human-induced ecosystem changes.

Pump Slice Amplitudes: A Simple and Robust Method for Connecting Two-Dimensional Infrared and Fourier Transform Infrared Spectra.

Ultrafast two-dimensional infrared (2D IR) spectroscopy and Fourier transform infrared (FTIR) spectroscopy are often performed in tandem, with FTIR typically used to interpret and provide hypotheses for 2D IR experiments. Comparisons between 2D IR and FTIR spectra can also be used to examine the structure and orientation in systems of coupled vibrational chromophores. The most common method for comparing 2D IR and FTIR lineshapes, the diagonal slice method, contains significant artifacts when applied to oscillators with low anharmonicities. Here, we introduce a new technique, the pump slice amplitude (PSA) method, for relating 2D IR lineshapes to FTIR lineshapes and compare PSAs against diagonal slices using theoretical and experimental spectra. We find that PSAs are significantly more similar to FTIR lineshapes than diagonal slices in systems with low anharmonicity.

Calcium-Lipid Interactions Observed with Isotope-Edited Infrared Spectroscopy.

Calcium ions bind to lipid membranes containing anionic lipids; however, characterizing the specific ion-lipid interactions in multicomponent membranes has remained challenging because it requires nonperturbative lipid-specific probes. Here, using a combination of isotope-edited infrared spectroscopy and molecular dynamics simulations, we characterize the effects of a physiologically relevant (2 mM) Ca2+ concentration on zwitterionic phosphatidylcholine and anionic phosphatidylserine lipids in mixed lipid membranes. We show that Ca2+ alters hydrogen bonding between water and lipid headgroups by forming a coordination complex involving the lipid headgroups and water. These interactions distort interfacial water orientations and prevent hydrogen bonding with lipid ester carbonyls. We demonstrate, experimentally, that these effects are more pronounced for the anionic phosphatidylserine lipids than for zwitterionic phosphatidylcholine lipids in the same membrane.

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

BACKGROUND: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. METHODS: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. RESULTS: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. CONCLUSIONS: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). LAY SUMMARY: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

The AAA ATPase Afg1 preserves mitochondrial fidelity and cellular health by maintaining mitochondrial matrix proteostasis.

Mitochondrial functions are critical for cellular physiology; therefore, several conserved mechanisms are in place to maintain the functional integrity of mitochondria. However, many of the molecular details and components involved in ensuring mitochondrial fidelity remain obscure. Here, we identify a novel role for the conserved mitochondrial AAA ATPase Afg1 in mediating mitochondrial protein homeostasis during aging and in response to various cellular challenges. Saccharomyces cerevisiae cells lacking functional Afg1 are hypersensitive to oxidative insults, unable to tolerate protein misfolding in the matrix compartment and exhibit progressive mitochondrial failure as they age. Loss of the Afg1 ortholog LACE-1 in Caenorhabditis elegans is associated with reduced lifespan, impeded oxidative stress tolerance, impaired mitochondrial proteostasis in the motor neuron circuitry and altered behavioral plasticity. Our results indicate that Afg1 is a novel protein quality control factor, which plays an important evolutionarily conserved role in mitochondrial surveillance, and cellular and organismal health.

The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs.

BACKGROUND: Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed "type-2 high" asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated. OBJECTIVE: The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine-induced signal transduction, airway inflammation, and mucus metaplasia in the lungs. METHODS: Wild-type (WT) and RAGE knockout (RAGE-/-) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine-induced effects. RESULTS: Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE-/- mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells. CONCLUSIONS: This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2-high asthma.

Physiological Calcium Concentrations Slow Dynamics at the Lipid-Water Interface.

Phospholipids can interact strongly with ions at physiological concentrations, and these interactions can alter membrane properties. Here, we describe the effects of calcium ions on the dynamics in phospholipid membranes. We used a combination of time-resolved ultrafast two-dimensional infrared spectroscopy and molecular dynamics simulations. We found that millimolar Ca2+ concentrations lead to slower fluctuations in the local environment at the lipid-water interface of membranes with phosphatidylserine. The effect was only observed in bilayers containing anionic phosphatidylserine; membranes composed of only zwitterionic phosphatidylcholine did not experience a slowdown. Local water dynamics were measured using the ester groups as label-free probes and were found to be up to 50% slower with 2.5 mM Ca2+. Molecular dynamics simulations show that Ca2+ primarily binds to the carboxylate group of phosphatidylserines. These findings have implications for apoptotic and diseased cells in which phosphatidylserine is exposed to extracellular calcium and for the biophysical effects of divalent cations on lipid bilayers.

Endogenous cannabinoids mediate the effect of BDNF at CA1 inhibitory synapses in the hippocampus.

Brain-derived neurotrophic factor (BDNF), traditionally known for promoting neuronal growth and development, is also a modulator of synaptic transmission. In addition to the well-characterized effects at excitatory synapses, BDNF has been shown to acutely suppress inhibitory neurotransmission; however, the underlying mechanisms are unclear. We have previously shown that at inhibitory synapses in layer 2/3 of the somatosensory cortex, BDNF induces the mobilization of endogenous cannabinoids (eCBs) that act retrogradely to suppress GABA release. Here, we hypothesized that in the hippocampus, BDNF acts similarly via eCB signaling to suppress GABAergic transmission. We found that the acute application of BDNF reduced the spontaneous inhibitory postsynaptic currents (sIPSCs) via postsynaptic TrkB receptor activation. The suppressive effects of BDNF required eCB signaling, as this effect on sIPSCs was prevented by a CB1 receptor antagonist. Further, blocking the postsynaptic eCB release prevented the effect of BDNF, whereas eCB reuptake inhibition enhanced the effect of BDNF. These results suggest that BDNF triggers the postsynaptic release of eCBs. To identify the specific eCB release by BDNF, we tested the effects of disrupting the synthesis or degradation of 2-arachidonoylcglycerol (2-AG). Blocking 2-AG synthesis prevented the effect of BDNF and blocking 2-AG degradation enhanced the effect of BDNF. However, there was no change in the effect of BDNF when anandamide degradation was blocked. Collectively, these results suggest that in the hippocampus, BDNF-TrkB signaling induces the postsynaptic release of the endogenous cannabinoid 2-AG, which acts retrogradely on the presynaptic CB1 receptors to suppress GABA release.

BDNF-induced endocannabinoid release modulates neocortical glutamatergic neurotransmission.

Endocannabinoids (eCBs) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent neuromodulators found throughout the mammalian neocortex. Both eCBs and BDNF play critical roles in many behavioral and neurophysiological processes and are targets for the development of novel therapeutics. The effects of eCBs and BDNF are primarily mediated by the type 1 cannabinoid (CB1) receptor and the trkB tyrosine kinase receptor, respectively. Our laboratory and others have previously established that BDNF potentiates excitatory transmission by enhancing presynaptic glutamate release and modulating NMDA receptors. In contrast, we have shown that BDNF attenuates inhibitory transmission by inducing postsynaptic release of eCBs that act retrogradely to suppress GABA release in layer 2/3 of somatosensory cortex. Here, we hypothesized that BDNF also induces release of eCBs at excitatory synapses, which could have a mitigating or opposing effect on the direct presynaptic effects of BDNF. We found the highest levels of expression of CB1 and trkB and receptors in layers 2/3 and 5. Surprisingly, BDNF did not increase the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) onto layer 5 pyramidal neurons in somatosensory cortex, in contrast to its effects in the hippocampus and visual cortex. However, the effect of BDNF on mEPSC frequency in somatosensory cortex was unmasked by blocking CB1 receptors or disrupting eCB release. Thus, BDNF-trKB signaling regulates glutamate release in the somatosensory cortex via opposing effects, a direct presynaptic enhancement of release probability, and simultaneous postsynaptically-induced eCB release that decreases release probability via presynaptic CB1 receptors.