Lateral orbitofrontal cortex promotes trial-by-trial learning of risky, but not spatial, biases

Individual choices are not made in isolation but are embedded in a series of past experiences, decisions, and outcomes. The effects of past experiences on choices, often called sequential biases, are ubiquitous in perceptual and value-based decision-making, but their neural substrates are unclear. We trained rats to choose between cued guaranteed and probabilistic rewards in a task in which outcomes on each trial were independent. Behavioral variability often reflected sequential effects, including increased willingness to take risks following risky wins, and spatial ‘win-stay/lose-shift’ biases. Recordings from lateral orbitofrontal cortex (lOFC) revealed encoding of reward history and receipt, and optogenetic inhibition of lOFC eliminated rats’ increased preference for risk following risky wins, but spared other sequential effects. Our data show that different sequential biases are neurally dissociable, and the lOFC’s role in adaptive behavior promotes learning of more abstract biases (here, biases for the risky option), but not spatial ones

Sources of noise during accumulation of evidence in unrestrained and voluntarily head-restrained rats

Abstract Decision-making behavior is often characterized by substantial variability, but its source remains unclear. We developed a visual accumulation of evidence task designed to quantify sources of noise and to be performed during voluntary head restraint, enabling cellular resolution imaging in future studies. Rats accumulated discrete numbers of flashes presented to the left and right visual hemifields and indicated the side that had the greater number of flashes. Using a signaldetection theory-based model, we found that the standard deviation in their internal estimate of flash number scaled linearly with the number of flashes. This indicates a major source of noise that, surprisingly, is not consistent with the widely used 'drift-diffusion modeling' (DDM) approach but is instead closely related to proposed models of numerical cognition and counting. We speculate that this form of noise could be important in accumulation of evidence tasks generally

Beyond traditional understanding of gender measurement: the gender (re)presentation approach

This paper considers different approaches to measuring gender. It critically reviews gender role theorising and describes how this has informed two approaches to measuring gender as an individual phenomenon: gender orientation (the assessment of individual traits) and gender ideology (assessing individual endorsement, and internalisation, of social norms). It is argued here that social constructionist perspectives offer a viable alternative to gender role theory and that these inform an alternative approach to measuring gender as a social phenomenon: gender (re)presentation. This approach assesses group level endorsement of dominant gender representations. Endorsement is not seen to reflect individual traits or internalised social norms. Rather, it is understood as a social practice, made meaningful through shared understanding of dominant gender representation. This approach is introduced through a critique of the traditional concept of attitudes and a reformulation thereof. The practical measurement implications and benefit of this reformulation are outlined

Optogenetic feedback control of neural activity

Optogenetic techniques enable precise excitation and inhibition of firing in specified neuronal populations and artifact-free recording of firing activity. Several studies have suggested that optical stimulation provides the precision and dynamic range requisite for closed-loop neuronal control, but no approach yet permits feedback control of neuronal firing. Here we present the ‘optoclamp’, a feedback control technology that provides continuous, real-time adjustments of bidirectional optical stimulation in order to lock spiking activity at specified targets over timescales ranging from seconds to days. We demonstrate how this system can be used to decouple neuronal firing levels from ongoing changes in network excitability due to multi-hour periods of glutamatergic or GABAergic neurotransmission blockade in vitro as well as impinging vibrissal sensory drive in vivo. This technology enables continuous, precise optical control of firing in neuronal populations in order to disentangle causally related variables of circuit activation in a physiologically and ethologically relevant manner.National Science Foundation (U.S.). Graduate Research FellowshipNational Science Foundation (U.S.). Integrative Graduate Education and Research Traineeshi

Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output

Neuronal activity in primary motor cortex (M1) correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B) pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed) firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1) a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons), and (2) a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons) that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior

Thalamic and extrathalamic mechanisms of consciousness after severe brain injury

Objective What mechanisms underlie the loss and recovery of consciousness after severe brain injury? We sought to establish, in the largest cohort of patients with disorders of consciousness (DOC) to date, the link between gold standard clinical measures of awareness and wakefulness, and specific patterns of local brain pathology-thereby possibly providing a mechanistic framework for patient diagnosis, prognosis, and treatment development. Methods Structural T1-weighted magnetic resonance images were collected, in a continuous sample of 143 severely brain-injured patients with DOC (and 96 volunteers) across 2 tertiary expert centers. Brain atrophy in subcortical regions (bilateral thalamus, basal ganglia, hippocampus, basal forebrain, and brainstem) was assessed across (1) healthy volunteers and patients, (2) clinical entities (eg, vegetative state, minimally conscious state) (3) clinical measures of consciousness (Coma Recovery Scale-Revised) and (4) injury etiology. Results Compared to volunteers, patients exhibited significant atrophy across all structures (p\u3c0.05, corrected). Strikingly, we found almost no significant differences across clinical entities. Nonetheless, the clinical measures of awareness and wakefulness upon which differential diagnosis rely were systematically associated with tissue atrophy within thalamic and basal ganglia nuclei, respectively; the basal forebrain was atrophied in proportion to patients\u27 response to sensory stimulation. In addition, nontraumatic injuries exhibited more extensive thalamic atrophy. Interpretation These findings provide, for the first time, a grounding in pathology for gold standard behavior-based clinical measures of consciousness, and reframe our current models of DOC by stressing the different links tying thalamic mechanisms to willful behavior and extrathalamic mechanisms to behavioral (and electrocortical) arousal

Recruitment of inhibition and excitation across mouse visual cortex depends on the hierarchy of interconnecting areas

Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relative recruitment of inhibitory and excitatory neurons within an area controls the gain of neurons for appropriate stimulus coding. We examined how such a balance of inhibition and excitation is differentially recruited across multiple levels of a cortical hierarchy by mapping the locations and strengths of synaptic inputs to pyramidal and parvalbumin (PV)-expressing neurons in feedforward and feedback pathways interconnecting primary (V1) and two higher visual areas. While interareal excitation was stronger in PV than in pyramidal neurons in all layer 2/3 pathways, we observed a gradual scaling down of the inhibition/excitation ratio from the most feedforward to the most feedback pathway. Our results indicate that interareal gain control depends on the hierarchical position of the source and the target, the direction of information flow through the network, and the laminar location of target neurons. DOI: http://dx.doi.org/10.7554/eLife.19332.00

Thalamic reticular nucleus induces fast and local modulation of arousal state

During low arousal states such as drowsiness and sleep, cortical neurons exhibit rhythmic slow wave activity associated with periods of neuronal silence. Slow waves are locally regulated, and local slow wave dynamics are important for memory, cognition, and behaviour. While several brainstem structures for controlling global sleep states have now been well characterized, a mechanism underlying fast and local modulation of cortical slow waves has not been identified. Here, using optogenetics and whole cortex electrophysiology, we show that local tonic activation of thalamic reticular nucleus (TRN) rapidly induces slow wave activity in a spatially restricted region of cortex. These slow waves resemble those seen in sleep, as cortical units undergo periods of silence phase-locked to the slow wave. Furthermore, animals exhibit behavioural changes consistent with a decrease in arousal state during TRN stimulation. We conclude that TRN can induce rapid modulation of local cortical state.National Institutes of Health (U.S.) (TR01 GM104948)Canadian Institutes of Health Research (Fellowship)Harvard University. Society of Fellows (Fellowship

Low incidence of new biochemical and clinical hypogonadism following hypofractionated stereotactic body radiation therapy (SBRT) monotherapy for low- to intermediate-risk prostate cancer

<p>Abstract</p> <p>Background</p> <p>The CyberKnife is an appealing delivery system for hypofractionated stereotactic body radiation therapy (SBRT) because of its ability to deliver highly conformal radiation therapy to moving targets. This conformity is achieved via 100s of non-coplanar radiation beams, which could potentially increase transitory testicular irradiation and result in post-therapy hypogonadism. We report on our early experience with CyberKnife SBRT for low- to intermediate-risk prostate cancer patients and assess the rate of inducing biochemical and clinical hypogonadism.</p> <p>Methods</p> <p>Twenty-six patients were treated with hypofractionated SBRT to a dose of 36.25 Gy in 5 fractions. All patients had histologically confirmed low- to intermediate-risk prostate adenocarcinoma (clinical stage ≤ T2b, Gleason score ≤ 7, PSA ≤ 20 ng/ml). PSA and total testosterone levels were obtained pre-treatment, 1 month post-treatment and every 3 months thereafter, for 1 year. Biochemical hypogonadism was defined as a total serum testosterone level below 8 nmol/L. Urinary and gastrointestinal toxicity was assessed using Common Toxicity Criteria v3; quality of life was assessed using the American Urological Association Symptom Score, Sexual Health Inventory for Men and Expanded Prostate Cancer Index Composite questionnaires.</p> <p>Results</p> <p>All 26 patients completed the treatment with a median 15 months (range, 13-19 months) follow-up. Median pre-treatment PSA was 5.75 ng/ml (range, 2.3-10.3 ng/ml), and a decrease to a median of 0.7 ng/ml (range, 0.2-1.8 ng/ml) was observed by one year post-treatment. The median pre-treatment total serum testosterone level was 13.81 nmol/L (range, 5.55 - 39.87 nmol/L). Post-treatment testosterone levels slowly decreased with the median value at one year follow-up of 10.53 nmol/L, significantly lower than the pre-treatment value (<it>p </it>< 0.013). The median absolute fall was 3.28 nmol/L and the median percent fall was 23.75%. There was no increase in biochemical hypogonadism at one year post-treatment. Average EPIC sexual and hormonal scores were not significantly changed by one year post-treatment.</p> <p>Conclusions</p> <p>Hypofractionated SBRT offers the radiobiological benefit of a large fraction size and is well-tolerated by men with low- to intermediate-risk prostate cancer. Early results are encouraging with an excellent biochemical response. The rate of new biochemical and clinical hypogonadism was low one year after treatment.</p