Causal evidence for cholinergic stabilization of attractor landscape dynamics.

There is substantial evidence that neuromodulatory systems critically influence brain state dynamics; however, most work has been purely descriptive. Here, we quantify, using data combining local inactivation of the basal forebrain with simultaneous measurement of resting-state fMRI activity in the macaque, the causal role of long-range cholinergic input to the stabilization of brain states in the cerebral cortex. Local inactivation of the nucleus basalis of Meynert (nbM) leads to a decrease in the energy barriers required for an fMRI state transition in cortical ongoing activity. Moreover, the inactivation of particular nbM sub-regions predominantly affects information transfer in cortical regions known to receive direct anatomical projections. We demonstrate these results in a simple neurodynamical model of cholinergic impact on neuronal firing rates and slow hyperpolarizing adaptation currents. We conclude that the cholinergic system plays a critical role in stabilizing macroscale brain state dynamics.

A Possible Neural Basis for Attentional Capture of Faces Revealed by Functional Magnetic Resonance Imaging and Causal Pharmacological Inactivation in Macaques.

In primates, the presence of a face in a visual scene captures attention and rapidly directs the observer's gaze to the face, even when the face is not relevant to the task at hand. Here, we explored a neural circuit that might potentially play a causal role in this powerful behavior. In our previous research, two monkeys received microinfusions of muscimol, a GABAA-receptor agonist, or saline (as a control condition) in separate sessions into individual or pairs of four inferotemporal face patches (middle and anterior lateral and fundal), as identified by a preceding face localizer experiment. Then, using fMRI, we measured the impact of each inactivation condition on responses in the other face patches relative to the control condition. In this study, we used the same method and measured the impact of each inactivation condition on responses in the FEF and the lateral intraparietal area, two regions associated with attentional processing, while face and nonface object stimuli were viewed. Our results revealed potential relationships between inferotemporal face patches and these two attention-related regions: The inactivation of the middle lateral and anterior fundal face patches had a pronounced impact on FEF, whereas the inactivation of the middle and anterior lateral face patches might have a noticeable influence on lateral intraparietal area. Together, these initial exploratory findings document a circuit that potentially underlies the attentional capture of faces. Confirmation of the role of this circuit remains to be accomplished in the context of paradigm explicitly testing the attentional capture of faces.

Bidirectional and parallel relationships in macaque face circuit revealed by fMRI and causal pharmacological inactivation.

Although the presence of face patches in primate inferotemporal (IT) cortex is well established, the functional and causal relationships among these patches remain elusive. In two monkeys, muscimol was infused sequentially into each patch or pair of patches to assess their respective influence on the remaining IT face network and the amygdala, as determined using fMRI. The results revealed that anterior face patches required input from middle face patches for their responses to both faces and objects, while the face selectivity in middle face patches arose, in part, from top-down input from anterior face patches. Moreover, we uncovered a parallel fundal-lateral functional organization in the IT face network, supporting dual routes (dorsal-ventral) in face processing within IT cortex as well as between IT cortex and the amygdala. Our findings of the causal relationship among the face patches demonstrate that the IT face circuit is organized into multiple functional compartments.

Methods for mechanical delivery of viral vectors into rhesus monkey brain.

BACKGROUND: Modern molecular tools make it possible to manipulate neural activity in a reversible and cell-type specific manner. For rhesus monkey research, molecular tools are generally introduced via viral vectors. New instruments designed specifically for use in monkey research are needed to enhance the efficiency and reliability of vector delivery. NEW METHOD: A suite of multi-channel injection devices was developed to permit efficient and uniform vector delivery to cortical regions of the monkey brain. Manganese was co-infused with virus to allow rapid post-surgical confirmation of targeting accuracy using MRI. A needle guide was designed to increase the accuracy of sub-cortical targeting using stereotaxic co-ordinates. RESULTS: The multi-channel injection devices produced dense, uniform coverage of dorsal surface cortex, ventral surface cortex, and intra-sulcal cortex, respectively. Co-infusion of manganese with the viral vector allowed for immediate verification of injection accuracy. The needle guide improved accuracy of targeting sub-cortical structures by preventing needle deflection. COMPARISON WITH EXISTING METHOD(S): The current methods, hand-held injections or single slow mechanical injection, for surface cortex transduction do not, in our hands, produce the density and uniformity of coverage provided by the injector arrays and associated infusion protocol. CONCLUSIONS: The efficiency and reliability of vector delivery has been considerably improved by the development of new methods and instruments. This development should facilitate the translation of chemo- and optogenetic studies performed in smaller animals to larger animals such as rhesus monkeys.

Tracking brain arousal fluctuations with fMRI.

Changes in brain activity accompanying shifts in vigilance and arousal can interfere with the study of other intrinsic and task-evoked characteristics of brain function. However, the difficulty of tracking and modeling the arousal state during functional MRI (fMRI) typically precludes the assessment of arousal-dependent influences on fMRI signals. Here we combine fMRI, electrophysiology, and the monitoring of eyelid behavior to demonstrate an approach for tracking continuous variations in arousal level from fMRI data. We first characterize the spatial distribution of fMRI signal fluctuations that track a measure of behavioral arousal; taking this pattern as a template, and using the local field potential as a simultaneous and independent measure of cortical activity, we observe that the time-varying expression level of this template in fMRI data provides a close approximation of electrophysiological arousal. We discuss the potential benefit of these findings for increasing the sensitivity of fMRI as a cognitive and clinical biomarker.

Oxytocin modulates fMRI responses to facial expression in macaques.

Increasing evidence has shown that oxytocin (OT), a mammalian hormone, modifies the way social stimuli are perceived and the way they affect behavior. Thus, OT may serve as a treatment for psychiatric disorders, many of which are characterized by dysfunctional social behavior. To explore the neural mechanisms mediating the effects of OT in macaque monkeys, we investigated whether OT would modulate functional magnetic resonance imaging (fMRI) responses in face-responsive regions (faces vs. blank screen) evoked by the perception of various facial expressions (neutral, fearful, aggressive, and appeasing). In the placebo condition, we found significantly increased activation for emotional (mainly fearful and appeasing) faces compared with neutral faces across the face-responsive regions. OT selectively, and differentially, altered fMRI responses to emotional expressions, significantly reducing responses to both fearful and aggressive faces in face-responsive regions while leaving responses to appeasing as well as neutral faces unchanged. We also found that OT administration selectively reduced functional coupling between the amygdala and areas in the occipital and inferior temporal cortex during the viewing of fearful and aggressive faces, but not during the viewing of neutral or appeasing faces. Taken together, our results indicate homologies between monkeys and humans in the neural circuits mediating the effects of OT. Thus, the monkey may be an ideal animal model to explore the development of OT-based pharmacological strategies for treating patients with dysfunctional social behavior.

Performance of galanin transgenic mice in the 5-choice serial reaction time attentional task.

The neuropeptide galanin impairs learning and memory in rodents. The mechanism underlying the cognitive effects of galanin may be related to inhibitory effects of galanin on cholinergic transmission. As cholinergic function is thought to modulate sustained attention, the present study examined whether galanin-overexpressing transgenic mice have impairments in sustained attention. Galanin transgenic (GAL-tg) mice and wild-type (WT) littermate controls were trained in a 5-choice serial reaction time task, modified to assess sustained attention. GAL-tg and WT mice performed similarly during acquisition with respect to accuracy, total omissions, and response speed. Attentional mechanisms were challenged by parametric changes including increased event rate, event asynchrony, or decreased stimulus duration. Singly, these challenges did not differentially affect performance between genotypes. Concurrent administration of these challenges, which represents an optimal test of sustained attention, also had similar effects on GAL-tg and WT mice. When stimulus discriminability was reduced by constant illumination of the house light, GAL-tg mice omitted more trials than WT mice, but other measures of performance did not differ by genotype. Moreover, intraventricular injection of galanin in WT mice did not affect sustained attention. These data indicate that previously reported learning and memory effects of galanin are not secondary to attentional dysfunction.