Perineuronal nets in the rat medial prefrontal cortex alter hippocampal-prefrontal oscillations and reshape cocaine self-administration memories.

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement in rodent models of cocaine use disorder. Output from the mPFC is potently modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). We previously showed that ABC treatment with chondroitinase ABC (ABC) reduced the consolidation and reconsolidation of a cocaine conditioned place preference (CPP) memory. However, self-administration memories are more difficult to disrupt. Here we report in male rats that ABC treatment in the mPFC attenuated the consolidation and blocked the reconsolidation of a cocaine self-administration memory. However, reconsolidation was blocked when rats were given a novel, but not familiar, type of retrieval session. Further, ABC treatment prior to, but not after, memory retrieval blocked reconsolidation. This same treatment did not alter a sucrose memory, indicating specificity for cocaine-induced memory. In naive rats, ABC treatment in the mPFC altered levels of PV intensity and cell firing properties. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during the novel retrieval session revealed that ABC prevented reward-associated increases in high-frequency oscillations and synchrony of these oscillations between the dHIP and mPFC. Together, this is the first study to show that ABC treatment disrupts reconsolidation of the original memory when combined with a novel retrieval session that elicits coupling between the dHIP and mPFC. This coupling after ABC treatment may serve as a fundamental signature for how to disrupt reconsolidation of cocaine memories and reduce relapse.Significance Statement Powerful memories are associated with drug-taking behavior over extended periods, and these memories can drive relapse to drugs of abuse. The medial prefrontal cortex (mPFC) is a major contributor to relapse in cocaine use disorder. In a well-established rodent model of cocaine use disorder, we identify how removal of key extracellular matrix structures called perineuronal nets (PNNs) within the mPFC reduces the ability to update a cocaine memory. We further show that the ABC treatment within the mPFC impairs the coupling of oscillations between the mPFC and dorsal hippocampus during the updating of cocaine memory. This impaired communication between mPFC and hippocampal circuitry may act as a signature for disrupting cocaine-related memories to help break the cycle of relapse.

Impact of changing climate on bryophyte contributions to terrestrial water, carbon, and nitrogen cycles.

Bryophytes, including the lineages of mosses, liverworts, and hornworts, are the second-largest photoautotroph group on Earth. Recent work across terrestrial ecosystems has highlighted how bryophytes retain and control water, fix substantial amounts of carbon (C), and contribute to nitrogen (N) cycles in forests (boreal, temperate, and tropical), tundra, peatlands, grasslands, and deserts. Understanding how changing climate affects bryophyte contributions to global cycles in different ecosystems is of primary importance. However, because of their small physical size, bryophytes have been largely ignored in research on water, C, and N cycles at global scales. Here, we review the literature on how bryophytes influence global biogeochemical cycles, and we highlight that while some aspects of global change represent critical tipping points for survival, bryophytes may also buffer many ecosystems from change due to their capacity for water, C, and N uptake and storage. However, as the thresholds of resistance of bryophytes to temperature and precipitation regime changes are mostly unknown, it is challenging to predict how long this buffering capacity will remain functional. Furthermore, as ecosystems shift their global distribution in response to changing climate, the size of different bryophyte-influenced biomes will change, resulting in shifts in the magnitude of bryophyte impacts on global ecosystem functions.

Perineuronal nets in the rat medial prefrontal cortex alter hippocampal-prefrontal oscillations and reshape cocaine self-administration memories.

The medial prefrontal cortex (mPFC) is a major contributor to relapse to cocaine in humans and to reinstatement behavior in rodent models of cocaine use disorder. Output from the mPFC is modulated by parvalbumin (PV)-containing fast-spiking interneurons, the majority of which are surrounded by perineuronal nets (PNNs). Here we tested whether chondroitinase ABC (ABC)- mediated removal of PNNs prevented the acquisition or reconsolidation of a cocaine self-administration memory. ABC injections into the dorsal mPFC prior to training attenuated the acquisition of cocaine self-administration. Also, ABC given 3 days prior to but not 1 hr after memory reactivation blocked cue-induced reinstatement. However, reduced reinstatement was present only in rats given a novel reactivation contingency, suggesting that PNNs are required for the updating of a familiar memory. In naive rats, ABC injections into mPFC did not alter excitatory or inhibitory puncta on PV cells but reduced PV intensity. Whole-cell recordings revealed a greater inter-spike interval 1 hr after ABC, but not 3 days later. In vivo recordings from the mPFC and dorsal hippocampus (dHIP) during novel memory reactivation revealed that ABC in the mPFC prevented reward-associated increases in beta and gamma activity as well as phase-amplitude coupling between the dHIP and mPFC. Together, our findings show that PNN removal attenuates the acquisition of cocaine self-administration memories and disrupts reconsolidation of the original memory when combined with a novel reactivation session. Further, reduced dHIP/mPFC coupling after PNN removal may serve as a key biomarker for how to disrupt reconsolidation of cocaine memories and reduce relapse.

Oxytocin receptors mediate oxytocin potentiation of methylphenidate-induced stimulation of accumbens dopamine in rats.

While the illicit use and misuse of stimulants like cocaine and methylphenidate (MP) has increased, there remains no FDA-approved treatments for psychostimulant use disorders (PSUD). Oxytocin (OT) has shown promise as a potential pharmacotherapy for PSUD. Dopamine (DA) neurotransmission plays a significant role in PSUD. We have recently shown that OT blunts the reinforcing effects of MP but, surprisingly, enhanced MP-induced stimulation of DA levels. Such effects have been suggested as a result of activation of OT receptors or, alternatively, could be mediated by direct actions of OT on MP blockade of the DA transporter. Here, we employed fast scan cyclic voltammetry (FSCV) to investigate the effects of systemic OT on MP-induced changes in the dynamics of DA, phasic release and uptake, in the nucleus accumbens shell (NAS) of Sprague-Dawley rats. We also tested the systemic effects of an antagonist of OT receptors, atosiban, to counteract the OT enhancement of dopaminergic effects of MP under microdialysis procedures in the NAS in rats. Administration of OT alone (2 mg/kg; i.p.) did not significantly modify evoked NAS DA dynamics measured by FSCV, and when administered 10 min before MP (0.1, 0.3, 1.0 mg/kg; i.v.), OT did not potentiate MP-induced increases in phasic DA release and did not alter DA clearance rate, suggesting no direct interactions of OT with the MP-induced blockade of DA uptake. Also, OT alone did not elicit significant changes in tonic, extracellular NAS DA levels measured by microdialysis. However, consistent with previous studies, we observed that OT pretreatments (2 mg/kg; i.p.) potentiated MP-induced (0.1, 0.3, 1.0 mg/kg; i.v.) efflux of extracellular NAS DA levels. This effect was abolished when rats were pretreated with atosiban (2 mg/kg; i.p.), suggesting that OT receptors mediate this OT action. Overall, our results suggest that OT receptors mediated OT potentiation of MP-induced stimulation of extracellular NAS DA levels, likely driven by modulation of DA receptor signaling pathways, without affecting MP blockade of DAT.

The Effects of Graded Protein Intake in Conjunction with Progressive Resistance Training on Skeletal Muscle Outcomes in Older Adults: A Preliminary Trial.

Many studies have evaluated the effects of resistance training (RT) and protein intake to attenuate the age-related loss of skeletal muscle. However, the effects of graded protein intake with conjunctive RT in older adults are unclear. Older adults (n = 18) performed 10 weeks of whole-body RT with progressions to intensity and volume while consuming either a constant protein (CP) diet (0.8−1.0 g/kg/d) with no protein supplement or a graded protein (GP) diet progressing from 0.8 g/kg/d at week 1 to 2.2 g/kg/d at week 10 with a whey protein supplement. Data were collected prior to commencement of the RT protocol (PRE), after week 5 (MID), and after week 10 (POST). Dual Energy X-ray Absorptiometry derived lean/soft tissue mass, ultrasonography derived muscle thickness, and a proxy of muscle quality were taken at PRE and POST, while isokinetic dynamometry derived peak torque were taken at PRE, MID, and POST. This study demonstrated the feasibility of the RT protocol (attendance = 96%), and protein intake protocol (CP in range all weeks; GP deviation from prescribed = 7%). Peak torque, muscle quality scores, and appendicular lean/soft tissue mass demonstrated the main effects of time (p < 0.05) while no other main effects of time or group * time interactions were seen for any measure. In conclusion, RT improved appendicular lean/soft tissue mass, peak torque, and muscle quality, with no differential effects of graded or constant protein intake.

Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

The number of individuals affected by psychostimulant use disorder (PSUD) has increased rapidly over the last few decades resulting in economic, emotional, and physical burdens on our society. Further compounding this issue is the current lack of clinically approved medications to treat this disorder. The dopamine transporter (DAT) is a common target of psychostimulant actions related to their use and dependence, and the recent availability of atypical DAT inhibitors as a potential therapeutic option has garnered popularity in this research field. Modafinil (MOD), which is approved for clinical use for the treatment of narcolepsy and sleep disorders, blocks DAT just like commonly abused psychostimulants. However, preclinical and clinical studies have shown that it lacks the addictive properties (in both behavioral and neurochemical studies) associated with other abused DAT inhibitors. Clinical availability of MOD has facilitated its off-label use for several psychiatric disorders related to alteration of brain dopamine (DA) systems, including PSUD. In this review, we highlight clinical and preclinical research on MOD and its R-enantiomer, R-MOD, as potential medications for PSUD. Given the complexity of PSUD, we have also reported the effects of MOD on psychostimulant-induced appearance of several symptoms that could intensify the severity of the disease (i.e., sleep disorders and impairment of cognitive functions), besides the potential therapeutic effects of MOD on PSUD.

Motivational interviewing education: Creation and assessment of a learning module implemented among advanced pharmacy practice students.

BACKGROUND AND PURPOSE: The purpose of this prospective nonrandomized study (quasi-experimental), pre-/post-intervention design was to implement and assess a formal orientation training program for Advanced Pharmacy Practice Experience (APPE) students focusing on skills related to motivational interviewing (MI). EDUCATIONAL ACTIVITY AND SETTING: Students were assessed on their knowledge, perceived ability, and perceived need to incorporate MI in practice using a pre-/posttest. Ability was assessed via student-conducted patient interviews, and performance was compared to published standards. Satisfaction with the training program was reviewed using a Likert scale questionnaire. Fourteen APPE students from three colleges of pharmacy were enrolled based on pre-assigned community experience placement. Students participated in a didactic training phase consisting of on-line knowledge acquisition and assessments. A modeling phase was implemented with role-play experiences and simulated video assessments. A shadowing phase was incorporated consisting of students observing a preceptor prior to independently conducting patient interviews. Interactions were audio recorded and reviewed by a preceptor with verbal and written feedback provided twice monthly using a standardized rubric. FINDINGS: Data revealed statistically significant improvements in all categories of the pre-/posttest. MI ability results showed statistically significant improvements as well. Performance scores were higher than goal values in video simulated assessments. Overall student satisfaction with the training program was 4.3 out of 5. DISCUSSION AND CONCLUSIONS: Data suggests the training program increased students understanding and ability to perform MI in patient interviews. High quality of student performance is also suggested due to trained students' post scores being higher than goal values published by scoring manual.

Global Health Education in Doctor of Pharmacy Programs.

The objective of this Review is to characterize content related to global health in didactic and experiential curricula of doctor of pharmacy (PharmD) programs in the United States. The review was completed through a systematic website search of 133 US PharmD programs accredited or currently in the process of obtaining accreditation to identify global health dual degrees, minors/concentrations, required and elective courses, and experiential opportunities. Programs' course catalogs were referenced as needed to find more specific course listings/descriptions. More than 50 programs offered an elective course related to global health; eight had a required course; eight offered a minor or certification for global health; three offered dual degrees in pharmacy and global health. Fourteen institutions had a center for global health studies on campus. More than 50 programs offered experiential education opportunities in global health including international advanced pharmacy practice experiences or medical mission trips. Inclusion of and focus on global health-related topics in US PharmD programs was widely varied.