Strength and Diversity of Inhibitory Signaling Differentiates Primate Anterior Cingulate from Lateral Prefrontal Cortex.

The lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC) of the primate play distinctive roles in the mediation of complex cognitive tasks. Compared with the LPFC, integration of information by the ACC can span longer timescales and requires stronger engagement of inhibitory processes. Here, we reveal the synaptic mechanism likely to underlie these differences using in vitro patch-clamp recordings of synaptic events and multiscale imaging of synaptic markers in rhesus monkeys. Although excitatory synaptic signaling does not differ, the level of synaptic inhibition is much higher in ACC than LPFC layer 3 pyramidal neurons, with a significantly higher frequency (∼6×) and longer duration of inhibitory synaptic currents. The number of inhibitory synapses and the ratio of cholecystokinin to parvalbumin-positive inhibitory inputs are also significantly higher in ACC compared with LPFC neurons. Therefore, inhibition is functionally and structurally more robust and diverse in ACC than in LPFC, resulting in a lower excitatory: inhibitory ratio and a greater dynamic range for signal integration and network oscillation by the ACC. These differences in inhibitory circuitry likely underlie the distinctive network dynamics in ACC and LPC during normal and pathological brain states.SIGNIFICANCE STATEMENT The lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC) play temporally distinct roles during the execution of cognitive tasks (rapid working memory during ongoing tasks and long-term memory to guide future action, respectively). Compared with LPFC-mediated tasks, ACC-mediated tasks can span longer timescales and require stronger engagement of inhibition. This study shows that inhibitory signaling is much more robust and diverse in the ACC than in the LPFC. Therefore, there is a lower excitatory: inhibitory synaptic ratio and a greater dynamic range for signal integration and oscillatory behavior in the ACC. These significant differences in inhibitory synaptic transmission form an important basis for the differential timing of cognitive processing by the LPFC and ACC in normal and pathological brain states.

Area-Specific Features of Pyramidal Neurons-a Comparative Study in Mouse and Rhesus Monkey.

A principal challenge of systems neuroscience is to understand the unique characteristics of cortical neurons and circuits that enable area- and species-specific sensory encoding, motor function, cognition, and behavior. To address this issue, we compared properties of layer 3 pyramidal neurons in 2 cortical areas that span a broad range of cortical function-primary sensory (V1), to cognitive (frontal)-in the mouse and the rhesus monkey. Hierarchical clustering and discriminant analyses of 15 physiological and 25 morphological variables revealed 2 fundamental principles. First, V1 and frontal neurons are remarkably similar with regard to nearly every property in the mouse, while the opposite is true in the monkey, with V1 and frontal neurons exhibiting significant differences in nearly every property assessed. Second, neurons within visual and frontal areas differ significantly between the mouse and the monkey. Neurons in mouse and monkey V1 are the same size, but differ in nearly every other way; mouse frontal cortical neurons are smaller than those in the monkey and also differ substantially with regard to most other properties. These findings have broad implications for understanding the differential contributions of heterogeneous neuronal types in construction of cortical microcircuitry in diverse brain areas and species.

Safety and pharmacokinetics of intravaginal rings delivering tenofovir in pig-tailed macaques.

Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel "pod IVR" platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 µg ml(-1) (slow releasing) and 1.84 ± 1.97 mg ml(-1) (fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 µg g(-1) and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/10(6) cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIV(SF162p3)) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.

Heatwaves, medications, and heat-related hospitalization in older Medicare beneficiaries with chronic conditions.

BACKGROUND: Heatwaves kill more people than floods, tornadoes, and earthquakes combined and disproportionally affect older persons and those with chronic conditions. Commonly used medications for chronic conditions, e.g., diuretics, antipsychotics disrupt thermoregulation or fluid/electrolyte balance and may sensitive patients to heat. However, the effect of heat-sensitizing medications and their interactions with heatwaves are not well-quantified. We evaluated effects of potentially heat-sensitizing medications in vulnerable older patients. METHODS: US Medicare data were linked at the zip code level to climate data with surface air temperatures for June-August of 2007-2012. Patients were Medicare beneficiaries aged ≥65 years with chronic conditions including diabetes, dementia, and cardiovascular, lung, or kidney disease. Exposures were potentially heat-sensitizing medications including diuretics, anticholinergics, antipsychotics, beta blockers, stimulants, and anti-hypertensives. A heatwave was defined as ≥2 days above the 95th percentile of historical zip code-specific surface air temperatures. We estimated associations of heat-sensitizing medications and heatwaves with heat-related hospitalization using self-controlled case series analysis. RESULTS: We identified 9,721 patients with at least one chronic condition and heat-related hospitalization; 42.1% of these patients experienced a heatwave. Heatwaves were associated with an increase in heat-related hospitalizations ranging from 21% (95% CI: 7% to 38%) to 33% (95% CI: 14% to 55%) across medication classes. Several drug classes were associated with moderately elevated risk of heat-related hospitalization in the absence of heatwaves, with rate ratios ranging from 1.16 (95% CI: 1.00 to 1.35) to 1.37 (95% CI: 1.14 to 1.66). We did not observe meaningful synergistic interactions between heatwaves and medications. CONCLUSIONS: Older patients with chronic conditions may be at heightened risk for heat-related hospitalization due to the use of heat-sensitizing medications throughout the summer months, even in the absence of heatwaves. Further studies are needed to confirm these findings and also to understand the effect of milder and shorter heat exposure.

An intravaginal ring for the simultaneous delivery of multiple drugs.

Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day⁻¹) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.