Behavioral variability through stochastic choice and its gating by anterior cingulate cortex.

Behavioral choices that ignore prior experience promote exploration and unpredictability but are seemingly at odds with the brain's tendency to use experience to optimize behavioral choice. Indeed, when faced with virtual competitors, primates resort to strategic counter prediction rather than to stochastic choice. Here, we show that rats also use history- and model-based strategies when faced with similar competitors but can switch to a "stochastic" mode when challenged with a competitor that they cannot defeat by counter prediction. In this mode, outcomes associated with an animal's actions are ignored, and normal engagement of anterior cingulate cortex (ACC) is suppressed. Using circuit perturbations in transgenic rats, we demonstrate that switching between strategic and stochastic behavioral modes is controlled by locus coeruleus input into ACC. Our findings suggest that, under conditions of uncertainty about environmental rules, changes in noradrenergic input alter ACC output and prevent erroneous beliefs from guiding decisions, thus enabling behavioral variation. PAPERCLIP:

Rapid and reversible chemical inactivation of synaptic transmission in genetically targeted neurons.

Inducible and reversible silencing of selected neurons in vivo is critical to understanding the structure and dynamics of brain circuits. We have developed Molecules for Inactivation of Synaptic Transmission (MISTs) that can be genetically targeted to allow the reversible inactivation of neurotransmitter release. MISTs consist of modified presynaptic proteins that interfere with the synaptic vesicle cycle when crosslinked by small molecule "dimerizers." MISTs based on the vesicle proteins VAMP2/Synaptobrevin and Synaptophysin induced rapid ( approximately 10 min) and reversible block of synaptic transmission in cultured neurons and brain slices. In transgenic mice expressing MISTs selectively in Purkinje neurons, administration of dimerizer reduced learning and performance of the rotarod behavior. MISTs allow for specific, inducible, and reversible lesions in neuronal circuits and may provide treatment of disorders associated with neuronal hyperactivity.

Monitoring synaptic transmission in primary neuronal cultures using local extracellular stimulation.

Various techniques have been applied for the functional analysis of synaptic transmission in cultured neurons. Here, we describe a method of studying synaptic transmission in neurons cultured at high-density from different brain regions such as the cortex, striatum and spinal cord. We use postsynaptic whole-cell recordings to monitor synaptic currents triggered by presynaptic action potentials that are induced by brief stimulations with a nearby extracellular bipolar electrode. Pharmacologically isolated excitatory or inhibitory postsynaptic currents can be reliably induced, with amplitudes, synaptic charge transfers, and short-term plasticity properties that are reproducible from culture to culture. We show that the size and kinetics of pharmacologically isolated inhibitory postsynaptic currents triggered by single action potentials or stimulus trains depend on the Ca2+ concentration, temperature and stimulation frequency. This method can be applied to study synaptic transmission in wildtype neurons infected with lentiviruses encoding various components of presynaptic release machinery, or in neurons from genetically modified mice, for example neurons carrying floxed genes in which gene expression can be acutely ablated by expression of Cre recombinase. The preparation described in this paper should be useful for analysis of synaptic transmission in inter-neuronal synapses formed by different types of neurons.

Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty.

Regions within the prefrontal cortex are thought to process beliefs about the world, but little is known about the circuit dynamics underlying the formation and modification of these beliefs. Using a task that permits dissociation between the activity encoding an animal's internal state and that encoding aspects of behavior, we found that transient increases in the volatility of activity in the rat medial prefrontal cortex accompany periods when an animal's belief is modified after an environmental change. Activity across the majority of sampled neurons underwent marked, abrupt, and coordinated changes when prior belief was abandoned in favor of exploration of alternative strategies. These dynamics reflect network switches to a state of instability, which diminishes over the period of exploration as new stable representations are formed.