Reward-related activity in the medial prefrontal cortex is driven by consumption

An emerging literature suggests that the medial prefrontal cortex (mPFC) is crucial for the ability to track behavioral outcomes over time and has a critical role in successful foraging. Here, we examine this issue by analyzing changes in neuronal spike activity and local field potentials in the rat mPFC in relation to the consumption of rewarding stimuli. Using multi-electrode recording methods, we simultaneously recorded from ensembles of neurons and field potentials in the mPFC during the performance of an operant-delayed alternation task and a variable-interval licking procedure. In both tasks, we found that consummatory behavior (licking) activates many mPFC neurons and is associated with theta-band phase locking by mPFC field potentials. Many neurons that were modulated by the delivery of reward were also modulated when rats emitted bouts of licks during the period of consumption. The majority of these licking-modulated neurons were found in the rostral part of the prelimbic cortex, a region that is heavily interconnected with the gustatory insular cortex and projects to subcortical feeding-related centers. Based on the tight coupling between spike activity, theta-band phase locking, and licking behavior, we suggest that reward-related activity in the mPFC is driven by consummatory behavior

Top-Down Control of Motor Cortex Ensembles by Dorsomedial Prefrontal Cortex

SummaryDorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding

Microfractures: A review

Microfractures are small, high-aspect-ratio cracks in rock that result from application of differential stresses. Although the term has been used to refer to larger features in the petroleum engineering and geophysics literature, in geologic parlance the term refers to fractures visible only under magnification, having lengths of millimeters or less and widths generally less than 0.1 mm. Nevertheless, populations of these structures typically encompass a wide size range and in some cases they form the small-size fraction of fracture arrays that include much larger factures. In geologic settings, microfractures commonly form as Mode I (opening) fractures where the minimum principal stress exceeds the elastic tensile strength creating a narrow opening displacement; in isotropic rocks such fractures mark the plane perpendicular to the least compressive principal stress during fracture growth. These planar or curviplanar openings provide an opportunity for fluids and/or gases to enter the created cavity. Cement deposits or crack closure may trap fluids or gases, leaving mineral precipitates and a track of enclosed fluids and gases. In transmitted light these precipitates frequently manifest as fluid-inclusion planes (FIPs). Cathodoluminescence (CL) images show that many are cement-filled microveins. Microfractures can be used to assess the paleostress history or fluid movement history of a rock body. Also, because sudden opening produces acoustic emissions, microfractures created in the laboratory can be used to assess the rock-failure process. Here we review recent discoveries made using microfractures, including fracture patterns, strain, fracture growth and size-scaling, evolution of stresses around propagating faults (process zones), far-field tectonic stresses, and insights into the state of stress leading to earthquakes

The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial

Background: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance. Methods/design: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression. Discussion: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM

Regulation of T Cell Priming by Lymphoid Stroma

The priming of immune T cells by their interaction with dendritic cells (DCs) in lymph nodes (LN), one of the early events in productive adaptive immune responses, occurs on a scaffold of lymphoid stromal cells, which have largely been seen as support cells or sources of chemokines and homeostatic growth factors. Here we show that murine fibroblastic reticular cells (FRCs), isolated from LN of B6 mice, play a more direct role in the immune response by sensing and modulating T cell activation through their upregulation of inducible nitric oxide synthase (iNOS) in response to early T cell IFNγ production. Stromal iNOS, which only functions in very close proximity, attenuates responses to inflammatory DC immunization but not to other priming regimens and preferentially affects Th1 cells rather than Th2. The resultant nitric oxide production does not affect T cell-DC coupling or initial calcium signaling, but restricts homotypic T cell clustering, cell cycle progression, and proliferation. Stromal feedback inhibition thus provides basal attenuation of T cell responses, particularly those characterized by strong local inflammatory cues

Enhanced Astrocytic Nitric Oxide Production and Neuronal Modifications in the Neocortex of a NOS2 Mutant Mouse

BACKGROUND: It has been well accepted that glial cells in the central nervous system (CNS) produce nitric oxide (NO) through the induction of a nitric oxide synthase isoform (NOS2) only in response to various insults. Recently we described rapid astroglial, NOS2-dependent, NO production in the neocortex of healthy mice on a time scale relevant to neuronal activity. To explore a possible role for astroglial NOS2 in normal brain function we investigated a NOS2 knockout mouse (B6;129P2-Nos2(tm1Lau)/J, Jackson Laboratory). Previous studies of this mouse strain revealed mainly altered immune responses, but no compensatory pathways and no CNS abnormalities have been reported. METHODOLOGY/PRINCIPAL FINDINGS: To our surprise, using NO imaging in brain slices in combination with biochemical methods we uncovered robust NO production by neocortical astrocytes of the NOS2 mutant. These findings indicate the existence of an alternative pathway that increases basal NOS activity. In addition, the astroglial mutation instigated modifications of neuronal attributes, shown by changes in the membrane properties of pyramidal neurons, and revealed in distinct behavioral abnormalities characterized by an increase in stress-related parameters. CONCLUSIONS/SIGNIFICANCE: The results strongly indicate the involvement of astrocytic-derived NO in modifying the activity of neuronal networks. In addition, the findings corroborate data linking NO signaling with stress-related behavior, and highlight the potential use of this genetic model for studies of stress-susceptibility. Lastly, our results beg re-examination of previous studies that used this mouse strain to examine the pathophysiology of brain insults, assuming lack of astrocytic nitrosative reaction