A Basal Ganglia Circuit Sufficient to Guide Birdsong Learning.

Learning vocal behaviors, like speech and birdsong, is thought to rely on continued performance evaluation. Whether candidate performance evaluation circuits in the brain are sufficient to guide vocal learning is not known. Here, we test the sufficiency of VTA projections to the vocal basal ganglia in singing zebra finches, a songbird species that learns to produce a complex and stereotyped multi-syllabic courtship song during development. We optogenetically manipulate VTA axon terminals in singing birds contingent on how the pitch of an individual song syllable is naturally performed. We find that optical inhibition and excitation of VTA terminals are each sufficient to reliably guide learned changes in song. Inhibition and excitation have opponent effects on future performances of targeted song syllables, consistent with positive and negative reinforcement of performance outcomes. These findings define a central role for reinforcement mechanisms in learning vocalizations and demonstrate minimal circuit elements for learning vocal behaviors. VIDEO ABSTRACT.

Identification of a motor-to-auditory pathway important for vocal learning.

Learning to vocalize depends on the ability to adaptively modify the temporal and spectral features of vocal elements. Neurons that convey motor-related signals to the auditory system are theorized to facilitate vocal learning, but the identity and function of such neurons remain unknown. Here we identify a previously unknown neuron type in the songbird brain that transmits vocal motor signals to the auditory cortex. Genetically ablating these neurons in juveniles disrupted their ability to imitate features of an adult tutor's song. Ablating these neurons in adults had little effect on previously learned songs but interfered with their ability to adaptively modify the duration of vocal elements and largely prevented the degradation of songs' temporal features that is normally caused by deafening. These findings identify a motor to auditory circuit essential to vocal imitation and to the adaptive modification of vocal timing.

The Structure, Thermodynamics and Solubility of Organic Crystals from Simulation with a Polarizable Force Field.

An important unsolved problem in materials science is prediction of the thermodynamic stability of organic crystals and their solubility from first principles. Solubility can be defined as the saturating concentration of a molecule within a liquid solvent, where the physical picture is of solvated molecules in equilibrium with their solid phase. Despite the importance of solubility in determining the oral bioavailability of pharmaceuticals, prediction tools are currently limited to quantitative structure-property relationships that are fit to experimental solubility measurements. For the first time, we describe a consistent procedure for the prediction of the structure, thermodynamic stability and solubility of organic crystals from molecular dynamics simulations using the polarizable multipole AMOEBA force field. Our approach is based on a thermodynamic cycle that decomposes standard state solubility into the sum of solid-vapor sublimation and vapor-liquid solvation free energies [Formula: see text], which are computed via the orthogonal space random walk (OSRW) sampling strategy. Application to the n-alkylamides series from aeetamide through octanamide was selected due to the dependence of their solubility on both amide hydrogen bonding and the hydrophobic effect, which are each fundamental to protein structure and solubility. On average, the calculated absolute standard state solubility free energies are accurate to within 1.1 kcal/mol. The experimental trend of decreasing solubility as a function of n-alkylamide chain length is recapitulated by the increasing stability of the crystalline state and to a lesser degree by decreasing favorability of solvation (i.e. the hydrophobic effect). Our results suggest that coupling the polarizable AMOEBA force field with an orthogonal space based free energy algorithm, as implemented in the program Force Field X, is a consistent procedure for predicting the structure, thermodynamic stability and solubility of organic crystals.

Automation of AMOEBA polarizable force field parameterization for small molecules.

A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database.