The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1).

Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinson's disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1(+/-) mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinson's disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1(+/-) mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1(+/-) mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia.

Distribution and structure of efferent synapses in the chicken retina.

The visual system of birds includes an efferent projection from a visual area, the isthmo-optic nucleus in the midbrain, back to the retina. Using a combination of anterograde labeling of efferent fibers, reconstruction of dye-filled neurons, NADPH-diaphorase staining, and transmission electron microscopy, we have examined the distribution of efferent fibers and their synaptic structures in the chicken retina. We show that efferent fibers terminate strictly within the ventral retina. In two completely mapped retinas, only 2 fibers from a total of 15,359 terminated in the dorsal retina. The major synapse made by each efferent fiber is with a single efferent target amacrine cell (TC). This synapse consists of 5-25 boutons of 2 microm diameter, each with multiple active zones, pressed into the TC soma or synapsing with a basketwork of rudimentary TC dendrites in the inner nuclear layer (INL). This basketwork, which is sheathed by Muller cell processes, defines a private neuropil in the INL within which TCs were also seen to receive input from retinal neurons. In addition to the major synapse, efferent fibers typically produce several very thin processes that terminate nearby in single small boutons and for which the soma of a local amacrine cell is one of the likely postsynaptic partners. A minority of efferent fibers also give rise to a thicker process, terminating in a strongly diaphorase-positive ball about 5 microm in diameter.

A potential screening technique for neurotransmitters in the CNS: model studies in the cat spinal cord.

This paper describes a potential screening technique for neurotransmitters in the CNS. The method uses the injection of small volumes of high specific activity radioactive transmitter precursor substances into regions of physiologically identified neuronal cell bodies, and the later identification of the substances transported down axons to target tissues. Experiments were performed in motoneurons in the cat spinal cords to test the feasibility of method. Tritiated choline, glutamate, tyramine and tryptophan were pressure-injected into the ventral horn using glass micropipettes that were adapted to allow similtaneous physiological recording and injection. Only tritiated acetylcholine, two unidentified choline metabolites and a small amount of choline were found in the motor axons. The acetylcholine migrated at a rate of greater than 24mm/day and the movement was blocked by colchicine. The spread of isotope from the injection site was measured by a direct chemical method and by autoradiography, and was found that isotope spread1-2 mm from the injection site. One unexpected finding in the autoradiographs was that the motoneurons were selectively labelled following choline injections.