The Role of the Rat Prefrontal Cortex and Sex Differences in Decision-Making.

The prefrontal cortex is critical for decision-making across species, with its activity linked to choosing between options. Drift Diffusion Models (DDMs) are commonly employed to understand the neural computations underlying this behavior. Studies exploring the specific roles of regions of the rodent prefrontal cortex in controlling the decision process are limited. This study explored the role of the prelimbic cortex (PLC) in decision-making using a two-alternative forced-choice task. Rats first learned to report the location of a lateralized visual stimulus. The brightness of the stimulus indicated its reward value. Then, the rats learned to make choices between pairs of stimuli. Sex differences in learning were observed, with females responding faster and more selectively to high-value stimuli than males. DDM analysis found that males had decreased decision thresholds during initial learning, whereas females maintained a consistently higher drift rate. Pharmacological manipulations revealed that PLC inactivation reduced the decision threshold for all rats, indicating that less information was needed to make a choice in the absence of normal PLC processing. Mu opioid receptor stimulation of the PLC had the opposite effect, raising the decision threshold and reducing bias in the decision process towards high-value stimuli. These effects were observed without any impact on the rats' choice preferences. Our findings suggest that PLC has an inhibitory role in the decision process and regulates the amount of evidence that is required to make a choice. That is, PLC activity controls "when", but not "how", to act.Significance Statement This study reports causal evidence for a part of the rat prefrontal cortex, the prelimbic cortex, in controlling the amount of information needed to make a choice. Results were based on reversible inactivation using the GABA-A agonist muscimol and by stimulation of mu opioid receptors using intra-cortical infusions of the selective mu agonist DAMGO. We also found evidence for a sex difference in learning and performing a visually guided two-alternative forced-choice task. Drift Diffusion Models found that females had stable decision processes throughout learning, and showed a persistent bias against the lower value option. By contrast, males exhibited changes in their decision processes, notably reducing the amount of information needed to make choice over the period of early choice learning.

Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior.

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy.SIGNIFICANCE STATEMENT The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy.

Medial Frontal Theta Is Entrained to Rewarded Actions.

Rodents lick to consume fluids. The reward value of ingested fluids is likely to be encoded by neuronal activity entrained to the lick cycle. Here, we investigated relationships between licking and reward signaling by the medial frontal cortex (MFC), a key cortical region for reward-guided learning and decision-making. Multielectrode recordings of spike activity and field potentials were made in male rats as they performed an incentive contrast licking task. Rats received access to higher- and lower-value sucrose rewards over alternating 30 s periods. They learned to lick persistently when higher-value rewards were available and to suppress licking when lower-value rewards were available. Spectral analysis of spikes and fields revealed evidence for reward value being encoded by the strength of phase-locking of a 6-12 Hz theta rhythm to the rats' lick cycle. Recordings during the initial acquisition of the task found that the strength of phase-locking to the lick cycle was strengthened with experience. A modification of the task, with a temporal gap of 2 s added between reward deliveries, found that the rhythmic signals persisted during periods of dry licking, a finding that suggests the MFC encodes either the value of the currently available reward or the vigor with which rats act to consume it. Finally, we found that reversible inactivations of the MFC in the opposite hemisphere eliminated the encoding of reward information. Together, our findings establish that a 6-12 Hz theta rhythm, generated by the rodent MFC, is synchronized to rewarded actions.SIGNIFICANCE STATEMENT The cellular and behavioral mechanisms of reward signaling by the medial frontal cortex (MFC) have not been resolved. We report evidence for a 6-12 Hz theta rhythm that is generated by the MFC and synchronized with ongoing consummatory actions. Previous studies of MFC reward signaling have inferred value coding upon temporally sustained activity during the period of reward consumption. Our findings suggest that MFC activity is temporally sustained due to the consumption of the rewarding fluids, and not necessarily the abstract properties of the rewarding fluid. Two other major findings were that the MFC reward signals persist beyond the period of fluid delivery and are generated by neurons within the MFC.

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.

A spiking neural integrator model of the adaptive control of action by the medial prefrontal cortex.

Subjects performing simple reaction-time tasks can improve reaction times by learning the expected timing of action-imperative stimuli and preparing movements in advance. Success or failure on the previous trial is often an important factor for determining whether a subject will attempt to time the stimulus or wait for it to occur before initiating action. The medial prefrontal cortex (mPFC) has been implicated in enabling the top-down control of action depending on the outcome of the previous trial. Analysis of spike activity from the rat mPFC suggests that neural integration is a key mechanism for adaptive control in precisely timed tasks. We show through simulation that a spiking neural network consisting of coupled neural integrators captures the neural dynamics of the experimentally recorded mPFC. Errors lead to deviations in the normal dynamics of the system, a process that could enable learning from past mistakes. We expand on this coupled integrator network to construct a spiking neural network that performs a reaction-time task by following either a cue-response or timing strategy, and show that it performs the task with similar reaction times as experimental subjects while maintaining the same spiking dynamics as the experimentally recorded mPFC.

Learning to Choose: Behavioral Dynamics Underlying the Initial Acquisition of Decision Making.

Current theories of decision making propose that decisions arise through competition between choice options. Computational models of the decision process estimate how quickly information about choice options is integrated and how much information is needed to trigger a choice. Experiments using this approach typically report data from well-trained participants. As such, we do not know how the decision process evolves as a decision-making task is learned for the first time. To address this gap, we used a behavioral design separating learning the value of choice options from learning to make choices. We trained male rats to respond to single visual stimuli with different reward values. Then, we trained them to make choices between pairs of stimuli. Initially, the rats responded more slowly when presented with choices. However, as they gained experience in making choices, this slowing reduced. Response slowing on choice trials persisted throughout the testing period. We found that it was specifically associated with increased exponential variability when the rats chose the higher value stimulus. Additionally, our analysis using drift diffusion modeling revealed that the rats required less information to make choices over time. Surprisingly, we observed reductions in the decision threshold after just a single session of choice learning. These findings provide new insights into the learning process of decision-making tasks. They suggest that the value of choice options and the ability to make choices are learned separately, and that experience plays a crucial role in improving decision-making performance.

The role of rat prelimbic cortex in decision making.

The frontal cortex plays a critical role in decision-making. One specific frontal area, the anterior cingulate cortex, has been identified as crucial for setting a threshold for how much evidence is needed before a choice is made (Domenech & Dreher, 2010). Threshold is a key concept in drift diffusion models, a popular framework used to understand decision-making processes. Here, we investigated the role of the prelimbic cortex, part of the rodent cingulate cortex, in decision making. Male and female rats learned to choose between stimuli associated with high and low value rewards. Females learned faster, were more selective in their responses, and integrated information about the stimuli more quickly. By contrast, males learned more slowly and showed a decrease in their decision thresholds during choice learning. Inactivating the prelimbic cortex in female and male rats sped up decision making without affecting choice accuracy. Drift diffusion modeling found selective effects of prelimbic cortex inactivation on the decision threshold, which was reduced with increasing doses of the GABA-A agonist muscimol. Stimulating the prelimbic cortex through mu opioid receptors slowed the animals' choice latencies and increased the decision threshold. These findings provide the first causal evidence that the prelimbic cortex directly influences decision processes. Additionally, they suggest possible sex-based differences in early choice learning.

Learning to Choose: Behavioral Dynamics Underlying the Initial Acquisition of Decision-Making.

Current theories of decision-making propose that decisions arise through competition between choice options. Computational models of the decision process estimate how quickly information about choice options is integrated and how much information is needed to trigger a choice. Experiments using this approach typically report data from well-trained participants. As such, we do not know how the decision process evolves as a decision-making task is learned for the first time. To address this gap, we used a behavioral design separating learning the value of choice options from learning to make choices. We trained male rats to respond to single visual stimuli with different reward values. Then, we trained them to make choices between pairs of stimuli. Initially, the rats responded more slowly when presented with choices. However, as they gained experience in making choices, this slowing reduced. Response slowing on choice trials persisted throughout the testing period. We found that it was specifically associated with increased exponential variability when the rats chose the higher value stimulus. Additionally, our analysis using drift diffusion modeling revealed that the rats required less information to make choices over time. These reductions in the decision threshold occurred after just a single session of choice learning. These findings provide new insights into the learning process of decision-making tasks. They suggest that the value of choice options and the ability to make choices are learned separately and that experience plays a crucial role in improving decision-making performance.

Lost in transition: aging-related changes in executive control by the medial prefrontal cortex.

Neural correlates of aging in the medial prefrontal cortex (mPFC) were studied using an operant delayed response task. The task used blocks of trials with memory-guided (delayed alternation) and visually-guided (stimulus-response) responding. Older rats (24 months) performed at a slow pace compared with younger rats (6 months). They wasted time engaged in nonessential behaviors (e.g., licking on spouts beyond the period of reward delivery) and were slow to respond at the end of the delay period. Aged mPFC neurons showed normal spatial processing. They differed from neurons in younger rats by having reduced modulations by imperative stimuli indicating reward availability and reduced activity associated with response latencies for reward collection. Older rats showed reduced sensitivity to imperative stimuli at three levels of neural activity: reduced fractions of neurons with changes in firing rate around the stimulus, reduced correlation over neurons at the time of the stimulus as measured with analysis of population activity, and reduced amplitudes of event-related fluctuations in intracortical field potentials at the time of the imperative stimulus. Our findings suggest that aging alters the encoding of time-sensitive information and impairs the ability of prefrontal networks to keep subjects "on task."

Open-source tools for behavioral video analysis: Setup, methods, and best practices.

Recently developed methods for video analysis, especially models for pose estimation and behavior classification, are transforming behavioral quantification to be more precise, scalable, and reproducible in fields such as neuroscience and ethology. These tools overcome long-standing limitations of manual scoring of video frames and traditional 'center of mass' tracking algorithms to enable video analysis at scale. The expansion of open-source tools for video acquisition and analysis has led to new experimental approaches to understand behavior. Here, we review currently available open-source tools for video analysis and discuss how to set up these methods for labs new to video recording. We also discuss best practices for developing and using video analysis methods, including community-wide standards and critical needs for the open sharing of datasets and code, more widespread comparisons of video analysis methods, and better documentation for these methods especially for new users. We encourage broader adoption and continued development of these tools, which have tremendous potential for accelerating scientific progress in understanding the brain and behavior.

Working with memory: evidence for a role for the medial prefrontal cortex in performance monitoring during spatial delayed alternation.

Neuronal spike activity was recorded in the medial prefrontal cortex (mPFC) as rats performed an operant spatial delayed alternation task. The sensitivities of neurons to choice, outcome, and temporal information-related aspects of the task were examined. About one-third of neurons were sensitive to the location of delayed responding while animals were at one of two spatially distinct response ports. However, many fewer neurons (<10%) maintained choice information over the delay, each exhibiting persistent differences in firing rates for only a portion of the delay. Another third of cells encoded information about behavioral outcomes, and some of these neurons (>20% of all cells) fired at distinct rates in advance of correct and incorrect responses (i.e., prospective encoding of outcome). Other cells were sensitive to reward-related feedback stimuli (>20%), the outcome of the preceding trial (retrospective encoding, 5-10%), and/or the time since a trial was last performed (10-20%). An anatomical analysis of the recording sites found that cells that were sensitive to choice, temporal, and outcome information were commingled within the middle layers of the mPFC. Together, our results suggest that spatial processing is only part of what drives mPFC neurons to become active during spatial working memory tasks. We propose that the primary role of mPFC in these tasks is to monitor behavioral performance by encoding information about recent trial outcomes to guide expectations and responses on the current trial. By encoding these variables, the mPFC is able to exert control over action and ensure that tasks are performed effectively and efficiently.

The rostral medial frontal cortex is crucial for engagement in consummatory behavior.

The medial frontal cortex (MFC) in rodents emits rhythmic activity that is entrained to the animal's licking cycle during consumption and encodes the value of consumed fluids. These signals are especially prominent in the rostral half of the MFC. This region is located above an orbitofrontal region where mu-opioid receptors regulate intake and reversible inactivation reduces behavioral measures associated with the incentive value and palatability of liquid sucrose. Here, we examined the effects of reversible inactivation and stimulation of mu-opioid receptors in rostral MFC on behavior in an incentive contrast licking task. Adult male rats licked to receive access to liquid sucrose, which alternated between high (16%) and low (4%) values over 30 s periods. Bilateral infusion of muscimol reduced the total number of licks over the 30 min test sessions, the time spent actively consuming sucrose, and the ratio of licks for the higher and lower value fluids. Inactivation did not alter licking frequency or variability or microstructural measures such as the duration of licking bouts that are classically associated with the palatability of a liquid reward. Infusions of [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO; 1 µg/µL) at the same sites had inconsistent behavioral effects across different subjects. Our findings suggest that the rostral MFC has a distinct role in the control of consummatory behavior and contributes to persistent consumption and not to the expression of palatability. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Noradrenergic regulation of two-armed bandit performance.

Reversal learning depends on cognitive flexibility. Many reversal learning studies assess cognitive flexibility based on the number of reversals that occur over a test session. Reversals occur when an option is repeatedly chosen, e.g., eight times in a row. This design feature encourages win-stay behavior and thus makes it difficult to understand how win-stay decisions influence reversal performance. We used an alternative design, reversals over blocks of trials independent of performance, to study how perturbations of the medial orbital cortex and the noradrenergic system influence reversal learning. We found that choice accuracy varies independently of win-stay behavior and the noradrenergic system controls sensitivity to positive feedback during reversal learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/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.

Coherent theta activity in the medial and orbital frontal cortices encodes reward value.

This study examined how the medial frontal (MFC) and orbital frontal (OFC) cortices process reward information. We simultaneously recorded local field potentials in the two areas as rats consumed liquid sucrose rewards. Both areas exhibited a 4-8 Hz 'theta' rhythm that was phase-locked to the lick cycle. The rhythm tracked shifts in sucrose concentrations and fluid volumes, demonstrating that it is sensitive to differences in reward magnitude. The coupling between the rhythm and licking was stronger in MFC than OFC and varied with response vigor and absolute reward value in the MFC. Spectral analysis revealed zero-lag coherence between the cortical areas, and found evidence for a directionality of the rhythm, with MFC leading OFC. Our findings suggest that consummatory behavior generates simultaneous theta range activity in the MFC and OFC that encodes the value of consumed fluids, with the MFC having a top-down role in the control of consumption.

Reward signaling by the rodent medial frontal cortex.

The anatomical relevance and functional significance of medial parts of the rodent frontal cortex have been intensely debated over the modern history of neuroscience. Early studies emphasized common functions among medial frontal regions in rodents and the dorsolateral prefrontal cortex of primates. Behavioral tasks emphasized memory-guided performance and persistent neural activity as a marker of working memory. Over time, it became clear that long-standing concerns about cross-species homology were justified and the view emerged that rodents are useful for understanding medial parts of the frontal cortex in primates, and not the dorsolateral prefrontal cortex. Here, we summarize a series of studies on the rodent medial frontal cortex that began with an interest in studying working memory in the perigenual prelimbic area and ended up studying reward processing in the medial orbital region. Our experiments revealed a role for a 4-8Hz "theta" rhythm in tracking engagement in the consumption of rewarding fluids and denoting the value of a given reward. Evidence for a functional differentiation between the rostral and caudal medial frontal cortex and its relationship to other frontal cortical areas is also discussed with the hope of motivating future work on this part of the cerebral cortex.

An Open Source Platform for Presenting Dynamic Visual Stimuli.

Operant behavior procedures often rely on visual stimuli to cue the initiation or secession of a response, and to provide a means for discriminating between two or more simultaneously available responses. While primate and human studies typically use Liquid-Crystal Display (LCD) or Organic Light-Emitting Diode (OLED) monitors and touch screens, rodent studies use a variety of methods to present visual cues ranging from traditional incandescent light bulbs, single LEDs, and, more recently, touch screen monitors. Commercially available systems for visual stimulus presentation are costly, challenging to customize, and are typically closed source. We developed an open-source, highly-modifiable visual stimulus presentation platform that can be combined with a 3D-printed operant response device. The device uses an 8 × 8 matrix of LEDs, and can be expanded to control much larger LED matrices. Implementing the platform is low-cost (<$70 USD per device in the year 2020). Using the platform, we trained rats to make nosepoke responses and discriminate between two distinct visual cues in a location-independent manner. This visual stimulus presentation platform is a cost-effective way to implement complex visually-guided operant behavior, including the use of moving or dynamically changing visual stimuli.

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.

The dorsomedial striatum reflects response bias during learning.

Previous studies have established that neurons in the dorsomedial striatum track the behavioral significance of external stimuli, are sensitive to contingencies between actions and outcomes, and show rapid flexibility in representing task-related information. Here, we describe how neural activity in the dorsomedial striatum changes during the initial acquisition of a Go/NoGo task and during an initial reversal of stimulus-response contingencies. Rats made nosepoke responses over delay periods and then received one of two acoustic stimuli. Liquid rewards were delivered after one stimulus (S+) if the rats made a Go response (entering a reward port on the opposite wall of the chamber). If a Go response was made to other stimulus (S-), rats experienced a timeout. On 10% of trials, no stimulus was presented. These trials were used to assess response bias, the animals' tendency to collect reward independent of the stimulus. Response bias increased during the reversal, corresponding to the animals' uncertainty about the stimulus-response contingencies. Most task-modulated neurons fired during the response at the end of the delay period. The fraction of response-modulated neurons was correlated with response bias and neural activity was sensitive to the behavioral response made on the previous trial. During initial task acquisition and initial reversal learning, there was a remarkable change in the percentages of neurons that fired in relation to the task events, especially during withdrawal from the nosepoke aperture. These results suggest that changes in task-related activity in the dorsomedial striatum during learning are driven by the animal's bias to collect rewards.

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.