Mark Laubach

Real-time prediction of hand trajectory by ensembles of cortical neurons in primates.

Signals derived from the rat motor cortex can be used for controlling one-dimensional movements of a robot arm. It remains unknown, however, whether real-time processing of cortical signals can be employed to reproduce, in a robotic device, the kind of complex arm movements used by primates to reach objects in space. Here we recorded the simultaneous activity of large populations of neurons, distributed in the premotor, primary motor and posterior parietal cortical areas, as non-human primates performed two distinct motor tasks. Accurate real-time predictions of one- and three-dimensional arm movement trajectories were obtained by applying both linear and nonlinear algorithms to cortical neuronal ensemble activity recorded from each animal. In addition, cortically derived signals were successfully used for real-time control of robotic devices, both locally and through the Internet. These results suggest that long-term control of complex prosthetic robot arm movements can be achieved by simple real-time transformations of neuronal population signals derived from multiple cortical areas in primates.

Neuronal basis of age-related working memory decline

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

Top-Down Control of Motor Cortex Ensembles by Dorsomedial Prefrontal Cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.

Imaging the spread of reversible brain inactivations using fluorescent muscimol

Muscimol is a GABA A-agonist that causes rapid and reversible suppression of neurophysiological activity. Interpretations of the effects of muscimol infusions into the brain have been limited because of uncertainty about spread of the drug around the injection site. To solve this problem, the present study explored the use of a fluorophore-conjugated muscimol molecule (FCM). Whole-cell recordings from horizontal brain slices demonstrated that bath-applied FCM acts like muscimol in reversibly suppressing excitatory synaptic transmission. Two types of in vivo experiments demonstrated that the behavioral effects of FCM infusion are similar to the behavioral effects of muscimol infusion. FCM infusion into the rat amygdala before fear conditioning impaired both cued and contextual freezing, which were tested 24 or 48 h later. Normal fear conditioning occurred when these same rats were subsequently given phosphate-buffered saline infusions. FCM infusion into the dorsomedial prefrontal cortex impaired accuracy during a delayed-response task. Histological analysis showed that the region of fluorescence was restricted to 0.5-1mm from the injection site. Myelinated fiber tracts acted as diffusional barriers, thereby shaping the overall spread of fluorescence. The results suggest that FCM is indeed useful for exploring the function of small brain regions.

Common medial frontal mechanisms of adaptive control in humans and rodents

In this report we describe how common brain networks within the medial frontal cortex (MFC) facilitate adaptive behavioral control in rodents and humans. We demonstrate that after errors, low-frequency oscillations below 12 Hz are modulated over the midfrontal cortex in humans and within the prelimbic and anterior cingulate regions of the MFC in rats. These oscillations were phase locked between the MFC and motor areas in both rats and humans. In rats, single neurons that encoded prior behavioral outcomes were phase coherent with low-frequency field oscillations, particularly after errors. Inactivating the medial frontal regions in rats led to impaired behavioral adjustments after errors, eliminated the differential expression of low-frequency oscillations after errors and increased low-frequency spike-field coupling within the motor cortex. Our results describe a new mechanism for behavioral adaptation through low-frequency oscillations and elucidate how medial frontal networks synchronize brain activity to guide performance.

Redundancy and Synergy of Neuronal Ensembles in Motor Cortex

We examined the ability of neuronal ensembles from rat motor cortex to predict behavioral performance during a reaction time task. We found that neurons that were the best individual predictors of task performance were not necessarily the neurons that contributed the most predictive information to an ensemble of neurons. To understand this result, we applied a framework for quantifying statistical relationships between neurons (Schneidman et al., 2003) to all possible combinations of neurons within our ensembles. We found that almost all neurons (96%) contributed redundant predictive information to the ensembles. This redundancy resulted in the maintenance of predictive information despite the removal of many neurons from each ensemble. Moreover, the balance of synergistic and redundant interactions depended on the number of neurons in the ensemble. Small ensembles could exhibit synergistic interactions (e.g., 23 ± 9% of ensembles with two neurons were synergistic). In contrast, larger ensembles exhibited mostly redundant interactions (e.g., 99 ± 0.1% of ensembles with eight neurons were redundant). We discuss these results with regard to constraints on interpreting neuronal ensemble data and with respect to motor cortex involvement in reaction time performance.

Dynamic encoding of action selection by the medial striatum.

Successful foragers respond flexibly to environmental stimuli. Behavioral flexibility depends on a number of brain areas that send convergent projections to the medial striatum, such as the medial prefrontal cortex, orbital frontal cortex, and amygdala. Here, we tested the hypothesis that neurons in the medial striatum are involved in flexible action selection, by representing changes in stimulus–reward contingencies. Using a novel Go/No-go reaction-time task, we changed the reward value of individual stimuli within single experimental sessions. We simultaneously recorded neuronal activity in the medial and ventral parts of the striatum of rats. The rats modified their actions in the task after the changes in stimulus–reward contingencies. This was preceded by dynamic modulations of spike activity in the medial, but not the ventral, striatum. Our results suggest that the medial striatum biases animals to collect rewards to potentially valuable stimuli and can rapidly influence flexible behavior.

Delay Activity in Rodent Frontal Cortex During a Simple Reaction Time Task

To understand how different parts of the frontal cortex control the timing of action, we characterized the firing patterns of single neurons in two areas of rodent frontal cortex-dorsomedial prefrontal cortex (dmPFC) and motor cortex-during a simple reaction time task. Principal component analysis was used to identify major patterns of delay-related activity in frontal cortex: ramping activity and sustained delay activity. These patterns were similar in dmPFC and motor cortex and did not change as animals learned to respond at novel delays. Many neurons in both areas were modulated early in the delay period. Other neurons were modulated in a persistent manner over the duration of the delay period. Delay-related modulations started earlier in motor cortex than in dmPFC and terminated around different task events (at the time of release in dmPFC, just before release of the lever in motor cortex). A subpopulation of neurons was found in dmPFC, but not motor cortex, that fired in response to the trigger stimulus. These results suggest that populations of neurons in rodent frontal cortex are coordinated during delay periods to enable proactive inhibitory control of action.

Neuronal Correlates of Post-Error Slowing in the Rat Dorsomedial Prefrontal Cortex

Rats with impaired function in dorsomedial regions of the prefrontal cortex (dmPFC) are unable to maintain a behavioral response over a delay period. Here we report that neurons in this cortical region are prominently modulated after errors in a tone-cued, simple reaction time task and that inactivation of dmPFC attenuates a slowing of reaction times that is observed following errors. Using methods for chronic single-unit recording, we found that approximately one-third of dmPFC neurons were modulated after errors, and 28% of these neurons had increased posterror firing that persisted into the delay period of the following trial. In contrast to dmPFC, no such neurons were found in motor cortex. Our results implicate the dorsomedial prefrontal cortex in a form of retrospective working memory that improves task performance following errors.

Regulation of Nucleus Accumbens Activity by the Hypothalamic Neuropeptide Melanin-Concentrating Hormone

The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer845) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through Gi/o, and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K+ channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.