Replicability in measures of attentional set-shifting task performance predicting chronic heavy drinking in rhesus monkeys.

This study was designed to replicate and extend a previous report that the increase in performance of an attentional set-shifting task (ASST) in rhesus monkeys predicted their future alcohol drinking status as a heavy drinker (HD) or non-heavy drinker (NHD). A cohort of 6 young adult male monkeys was trained and tested under the same ASST and then underwent a alcohol self-administration protocol that maintained open-access (22 hours/day) choice of alcohol or water 7 days/week for approximately 6 months. The average improvement in performance in the ASST, as measured by a performance index, was replicated in the cohort of 6 monkeys when compared to the increase in the task performance in a previous cohort of 9 male monkeys. The alcohol self-administration protocol was then used to determine the drinking status (HD: n = 4 or NHD: n = 2) of the replicate cohort, which was accurately predicted by the performance on the ASST. Finally, individuals from both cohorts could be combined based on future drinking status of HD (n = 8) or NHD (n = 7), and the association with pre-alcohol ASST performance remained. Specifically, monkeys that had lower rates of PI improvement were more likely to become HDs. To our knowledge, this is the first study to replicate that deficits in the set-shifting performance can predict chronic heavy alcohol drinking in primates.

LC-MS/MS measurement of endogenous oxytocin in the posterior pituitary and CSF of macaques: A pilot study.

Oxytocin (OT) is a nanopeptide released into systemic circulation via the posterior pituitary (peripheral) and into the central nervous system via widespread OTergic pathways (central). Central OT plays a significant role in variety of functions from social and executive cognition to immune regulation. Many ongoing studies explore its therapeutic potential for variety of neuropsychiatric disorders. Measures of peripheral OT levels are most frequently used as an indicator of its concentration in the central nervous system in humans and animal models. In this study, LC-MS/MS was used to measure OT in pituitary samples collected from adult male macaque monkeys in order to explore the correlation between individual levels of OT in the CSF (central) and pituitary (peripheral). We quantified individual differences in the levels of OT in the pituitaries (44-151 ng/mg) and CSF (41-66 pg/mL) of these monkeys. A positive correlation between these two measures was identified. These preliminary results allow for future analyses to determine whether LC-MS/MS measures of peripheral OT can be used as markers of OT levels in the brain of nonhuman primates that serve as valuable models for many human neuropsychiatric disorders.

Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques.

Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated. In this nonhuman primate study, we administer deuterated oxytocin intranasally and intravenously to rhesus macaques and measure, with mass spectrometry, concentrations of labeled (exogenously administered) and endogenous oxytocin in 12 brain regions two hours after oxytocin administration. Labeled oxytocin is quantified after intranasal (not intravenous) administration in brain regions (orbitofrontal cortex, striatum, brainstem, and thalamus) that lie in the trajectories of the olfactory and trigeminal nerves. These results suggest that intranasal administration bypasses the blood-brain barrier, delivering oxytocin to specific brain regions, such as the striatum, where oxytocin acts to impact motivated behaviors. Further, high concentrations of endogenous oxytocin are in regions that overlap with projection fields of oxytocinergic neurons.

Encoding of conditioned reflex activity in different directions by neurons in the monkey striatum.

Two types of neuron spike activity were detected in the striatum (putamen) of monkeys: patterns with low and high activity. Low-activity patterns were no more than twice the level of baseline activity, while high-activity patterns had larger factors. An individual neuron could generate different patterns during different actions. On performance of tasks requiring movement in different directions, the greatest differences in the sets of neurons with high-activity patterns were seen during preparation and onset of the movement in the chosen direction and on completion of the movement. Differences between the sets of neurons with low-activity patterns, conversely, decreased at these behavior stages. They were maximal before presentation of the conditioned signal, when the animal was still unaware of the task, and at the end of the program, when the alternative choice task had been completed. These data provide evidence that the encoding of signals reflecting the involvement of the striatum in solving the alternative choice task occurs by means of multilevel addressed signal encoding. The main role in this is played by changes in the set of neurons generating patterns of different levels of activity.

[Coding the differently directed behavioral actions by the putamen neurons of the monkey brain].

Spike activity related to the problem of alternative choice of behavioral actions was recorded in the putamen of the monkey brain. The patterns of low and high activities were identified. Each neuron during different behaviour actions could generate any kind of patterns. The differences between neuronal compositions with patterns of high activity, at the left and right direction of the task, were obtained during decision making about the movement direction, and also at the end of the movement. Distinctions between neuronal compositions with patterns of low activity at this time, on the contrary, diminished. The neuronal compositions with patterns of low activity were much more before the conditioned signal, when the animal did not yet know the task, and at the end of the program when the problem was already solved. The data obtained show that the putamen units control different directions of actions by a multilevel address coding, mainly through reorganizing the neuronal compositions with patterns of different level activity.

Dynamics of neuron activity levels in the monkey striatum associated with performance of a multistage behavioral program.

The levels of activity of monkey putamen neurons were studied during multistage behavior. Two groups of neuron activity patterns were identified. One was a pattern of low activity, less than twice the background level; the other was a pattern of high activity, exceeding the background by a greater factor. Neither type of pattern was linked with defined neurons, but both were associated with particular stages in the behavior. Low-activity patterns were recorded primarily at stages associated with the warning signal and receipt of the food reward at the stages completing the task. High-activity patterns were associated with the animal performing actions in response to the conditioned stimulus and with the decision-taking stage, when performance of the actions involved selection of the right or left hand. In addition, the number of these patterns increased significantly in relation to signals indicating correct performance of the task. Key moments in the behavior were found to be associated with increases in the numbers of high-activity patterns and simultaneous decreases in the number of low-activity patterns.

[The dynamics of neuron activity level in the striatum of the monkey brain in relation to the realization of multistage behavior].

Level of the unit activity was studied in the monkey putamen during multistage behavior. Two groups of neuron activity patterns were distinguished. The first one involved patterns of low level neuron activity less exceeding the background level than the second one; the other group involved patterns of high level neuron activity exceeding the background level in the second time. These kinds of patterns were behavior-related. Patterns with low level neuron activity were recorded preferentially in relation to the trigger stimuli and reward. Patterns of high level neuron activity were recorded in relation to the decision-making, movements of arms in the left and right directions. Besides, their number rose in relation to the auditory cue reported to right realization of the task. It was established that the number of patterns of high level neuron activity rose in key moments of behavior, while the number of the patterns of low level neuron activity decreased.