Max Kleiman-Weiner

Differential electrophysiological properties of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons

The electrophysiological properties of distinct subpopulations of striatal medium‐sized spiny neurons (MSSNs) were compared using enhanced green fluorescent protein as a reporter gene for identification of neurons expressing dopamine D1 and D2 receptor subtypes in mice. Whole‐cell patch‐clamp recordings in slices revealed that passive membrane properties were similar in D1 and D2 cells. All MSSNs displayed hyperpolarized resting membrane potentials but the threshold for firing action potentials was lower in D2 than in D1 neurons. In voltage clamp, the frequency of spontaneous excitatory postsynaptic currents was higher in D2 than in D1 cells and large‐amplitude inward currents (> 100 pA) were observed only in D2 cells. After tetrodotoxin this difference was reduced, suggesting that sodium conductances contribute to the increased frequencies in D2 cells. After pharmacological blockade of GABAA receptors, a subset of D2 cells also displayed large spontaneous membrane depolarizations and complex responses to stimulation of the corticostriatal pathway. To further characterize ionotropic glutamate receptor function, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) was applied onto dissociated MSSNs. Application of AMPA alone or in the presence of cyclothiazide (an AMPA receptor desensitization blocker) evoked larger currents in D1 than in D2 cells. Together, these data demonstrate significant differences in electrophysiological properties of subpopulations of MSSNs defined by selective expression of D1 and D2 receptors. D2 cells display increased excitability and reflect ongoing cortical activity more faithfully than D1 cells, an effect that is independent of postsynaptic AMPA receptors and probably results from stronger synaptic coupling. This could help to explain the increased vulnerability of D2 MSSNs in neurodegenerative disorders.

A gain in GABAA receptor synaptic strength in thalamus reduces oscillatory activity and absence seizures.

Neural inhibition within the thalamus is integral in shaping thalamocortical oscillatory activity. Fast, synaptic inhibition is primarily mediated by activation of heteropentameric GABAA receptor complexes. Here, we examined the synaptic physiology and network properties of mice lacking GABAA receptor α3, a subunit that in thalamus is uniquely expressed by inhibitory neurons of the reticular nucleus (nRT). Deletion of this subunit produced a powerful compensatory gain in inhibitory postsynaptic response in nRT neurons. Although, other forms of inhibitory and excitatory synaptic transmission in the circuit were unchanged, evoked thalamic oscillations were strongly dampened in α3 knockout mice. Furthermore, pharmacologically induced thalamocortical absence seizures displayed a reduction in length and power in α3 knockout mice. These studies highlight the role of GABAergic inhibitory strength within nRT in the maintenance of thalamic oscillations, and demonstrate that inhibitory intra-nRT synapses are a critical control point for regulating higher order thalamocortical network activity.

Anemia in Rural China's Elementary Schools: Prevalence and Correlates in Shaanxi Province's Poor Counties

Despite growing wealth in China, a significant share of children across rural China still have no access to iron-rich foods, vitamins, and other micronutrients. Such poor diets may result in high incidences of nutritional problems, including anemia. The objective of the study was to increase understanding of the extent of anemia, and identify structural correlates of anemia in poor Shaanxi provinces primary schools. The article shows that the overall anemia rate is 21.5 percent when using a blood hemoglobin cutoff of 115 g/L (39 percent with a cutoff of 120 g/L). We find that those students that are boarding at school and eat lunch away from home are more likely to be anemic. Children with anemia are found to have lower height for age (HAZ) scores. If this part of Shaanxi province is representative of all poor counties in China, these findings mean millions of children in poor rural China may be anemic.

Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.

In the R6/2 mouse model of Huntington’s disease (HD) we examined the effects of a number of behavioral and pharmacological manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor desensitization, slow deactivation, and facilitate glutamate release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic progression of HD in this model.

Synergistic roles of GABAA receptors and SK channels in regulating thalamocortical oscillations.

Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy. Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. One widely used model to understand the epileptiform oscillations underlying absence epilepsy involves application of bicuculline methiodide (BMI) to brain slices containing the thalamus. BMI is a well-known GABAA receptor blocker that has previously been discovered to also block small-conductance, calcium-activated potassium (SK) channels. Here we report that the robust epileptiform oscillations observed during BMI application rely synergistically on both GABAA receptor and SK channel antagonism. Neither application of picrotoxin, a selective GABAA receptor antagonist, nor application of apamin, a selective SK channel antagonist, alone yielded the highly synchronized, long-lasting oscillations comparable to those observed during BMI application. However, partial blockade of SK channels by subnanomolar concentrations of apamin combined with picrotoxin sufficiently replicated BMI oscillations. We found that, at the cellular level, apamin enhanced the intrinsic excitability of reticular nucleus (RT) neurons but had no effect on relay neurons. This work suggests that regulation of RT excitability by SK channels can influence the excitability of thalamocortical networks and may illuminate possible pharmacological treatments for absence epilepsy. Finally, our results suggest that changes in the intrinsic properties of individual neurons and changes at the circuit level can robustly modulate these oscillations.

Multiple Micronutrient Supplementation Reduces Anemia and Anxiety in Rural China’s Elementary School Children

Despite growing wealth and a strengthening government commitment to improve livelihoods and welfare, many students across rural China have inadequate access to micronutrient-rich diets. Poor diets can lead to nutritional problems, such as iron-deficiency anemia, that can adversely affect health, attention, learning, and mental health. The overall goal of this paper is to assess the impact of multiple micronutrient supplementation (MMS) on anemia and anxiety among students in poor areas of rural China. To achieve this goal, we conducted a randomized controlled trial in 54 randomly chosen elementary schools in 8 of the poorest counties in Shaanxi Province in Northwest China. Study participants were 2730 fourth-grade students, mostly aged 10-12 y. Schools were randomly assigned to 1 of 2 groups: a control group that received no intervention and an intervention group that received a daily MMS with 5 mg of iron (ferrous sulfate) for 5 mo. Our primary outcome measures were hemoglobin (Hb) concentrations (assessed by HemoCue 201+ technology), anemia prevalence (defined as Hb) concentrations ≤120 g/L), and anxiety (using a written mental health test). The results showed that 42.4% of students were anemic at baseline. The Hb concentration was 121.7 ± 10.7 g/L in the treatment group and 123.4 ± 11.4 g/L in the control group. MMS increased Hb concentrations by 1.7 g/L ± 0.15 and reduced anemia rates by 7.0 percentage points (P < 0.05). Anxiety was reduced by 0.30 SDs (P < 0.01). MMS reduced both anemia and anxiety. Our results should encourage further research on the linkages between nutrition and mental health in a development context.

Learning a commonsense moral theory

We introduce a computational framework for understanding the structure and dynamics of moral learning, with a focus on how people learn to trade off the interests and welfare of different individuals in their social groups and the larger society. We posit a minimal set of cognitive capacities that together can solve this learning problem: (1) an abstract and recursive utility calculus to quantitatively represent welfare trade-offs; (2) hierarchical Bayesian inference to understand the actions and judgments of others; and (3) meta-values for learning by value alignment both externally to the values of others and internally to make moral theories consistent with ones own attachments and feelings. Our model explains how children can build from sparse noisy observations of how a small set of individuals make moral decisions to a broad moral competence, able to support an infinite range of judgments and decisions that generalizes even to people they have never met and situations they have not been in or observed. It also provides insight into the causes and dynamics of moral change across time, including cases when moral change can be rapidly progressive, changing values significantly in just a few generations, and cases when it is likely to move more slowly.

Non‐parametric Bayesian inference of strategies in repeated games

Inferring underlying cooperative and competitive strategies from human behaviour in repeated games is important for accurately characterizing human behaviour and understanding how people reason strategically. Finite automata, a bounded model of computation, have been extensively used to compactly represent strategies for these games and are a standard tool in game theoretic analyses. However, inference over these strategies in repeated games is challenging since the number of possible strategies grows exponentially with the number of repetitions yet behavioural data are often sparse and noisy. As a result, previous approaches start by specifying a finite hypothesis space of automata that does not allow for flexibility. This limitation hinders the discovery of novel strategies that may be used by humans but are not anticipated a priori by current theory. Here we present a new probabilistic model for strategy inference in repeated games by exploiting non‐parametric Bayesian modelling. With simulated data, we show that the model is effective at inferring the true strategy rapidly and from limited data, which leads to accurate predictions of future behaviour. When applied to experimental data of human behaviour in a repeated prisoners dilemma, we uncover strategies of varying complexity and diversity.

Statistically inaccurate and morally unfair judgements via base rate intrusion

From a statistical standpoint, judgements about an individual are more accurate if base rates about the individual’s social group are taken into account1–4. But from a moral standpoint, using these base rates is considered unfair and can even be illegal5–9. Thus, the imperative to be statistically accurate is directly at odds with the imperative to be morally fair. This conflict was resolved by creating tasks in which Bayesian rationality and moral fairness were aligned, thereby allowing social judgements to be both accurate and fair. Despite this alignment, we show that social judgements were inaccurate and unfair. Instead of appropriately setting aside social group differences, participants erroneously relied on them when making judgements about specific individuals. This bias—which we call base rate intrusion—was robust, generalized across various social groups (gender, race, nationality and age), and differed from analogous non-social judgements. Results also demonstrate how social judgements can be corrected to achieve both statistical accuracy and moral fairness. Overall, these data (total N = 5,138) highlight the pernicious effects of social base rates: under conditions that closely approximate those of everyday life10–12, these base rates can undermine the rationality and fairness of human judgements.Cao et al. demonstrate that people systematically rely on social base rates when making judgements about individuals, even when these base rates are statistically irrelevant. The authors show that multiple remedies are required to eliminate this bias of base rate intrusion.