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. 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.

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.

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).

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.

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.

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.

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.

An Open Source Syringe Pump Controller for Fluid Delivery of Multiple Volumes.

Syringe pumps are a necessary piece of laboratory equipment that are used for fluid delivery in behavioral neuroscience laboratories. Many experiments provide rodents and primates with fluid rewards such as juice, water, or liquid sucrose. Current commercialized syringe pumps are not customizable and do not have the ability to deliver multiple volumes of fluid based on different inputs to the pump. Additionally, many syringe pumps are expensive and cannot be used in experiments with paired neurophysiological recordings due to electrical noise. We developed an open source syringe pump controller using commonly available parts. The controller adjusts the acceleration and speed of the motor to deliver three different volumes of fluid reward within one common time epoch. This syringe pump controller is cost effective and has been successfully implemented in rodent behavioral experiments with paired neurophysiological recordings in the rat frontal cortex while rats lick for different volumes of liquid sucrose rewards. Our syringe pump controller will enable new experiments to address the potential confound of temporal information in studies of reward signaling by fluid magnitude.

The rat medial frontal cortex controls pace, but not breakpoint, in a progressive ratio licking task.

The medial frontal cortex (MFC) is crucial for selecting actions and evaluating their outcomes. Outcome monitoring may be triggered by rostral parts of the MFC, which contain neurons that are modulated by reward consumption and are necessary for the expression of relative reward value. Here, we examined if the MFC further has a role in the control of instrumental licking. We used a progressive ratio licking task in which rats had to make increasing numbers of licks to receive liquid sucrose rewards. We determined what measures of progressive ratio performance are sensitive to value by testing rats with rewards containing 0%-16% sucrose. We found some measures (breakpoint, number of licking bouts) were sensitive to sucrose concentration and others (response rate, duration of licking bouts) were not. Then, we examined the effects of reversibly inactivating rostral (medial orbital) and caudal (prelimbic) parts of the MFC. We were surprised to find that inactivation had no effects on measures associated with value (e.g., breakpoint). Instead, inactivation altered behavioral measures associated with the pace of task performance (response rate and time to break). These effects depended on where inactivations were made. Response rates increased and time to break decreased when the caudal prelimbic area was inactivated. By contrast, response rates decreased and the time to break increased when the rostral medial orbital cortex was inactivated. Our findings suggest that the medial frontal cortex has a role in maintaining task engagement, but not in the motivational control of action, in the progressive ratio licking task. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

What, If Anything, Is Rodent Prefrontal Cortex?

Prefrontal cortex (PFC) means different things to different people. In recent years, there has been a major increase in publications on the PFC, especially using mice. However, inconsistencies in the nomenclature and anatomical boundaries of PFC areas has made it difficult for researchers to compare data and interpret findings across species. We conducted a meta-analysis of publications on the PFC of humans and rodents and found dramatic differences in the focus of research on these species. In addition, we compared anatomical terms and criteria across several common rodent brain atlases and found inconsistencies among, and even within, leading atlases. To assess the impact of these issues on the research community, we conducted a survey of established PFC researchers on their use of anatomical terms and found little consensus. We report on the results of the survey and propose an alternative scheme for interpreting data from rodent studies, based on structural analysis of the corpus callosum and nomenclature used in research on the anterior cingulate cortex (ACC) of primates.

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.

Inhibitory Control: Mapping Medial Frontal Cortex.

Functional anatomy in frontal cortex has been elusive and controversial. A new study combines neuronal ensemble recordings and optogenetics to map a functional gradient in rodent prefrontal cortex that supports inhibitory control.

Cholinergic and ghrelinergic receptors and KCNQ channels in the medial PFC regulate the expression of palatability.

The medial prefrontal cortex (mPFC) is a key brain region for the control of consummatory behavior. Neuronal activity in this area is modulated when rats initiate consummatory licking and reversible inactivations eliminate reward contrast effects and reduce a measure of palatability, the duration of licking bouts. Together, these data suggest the hypothesis that rhythmic neuronal activity in the mPFC is crucial for the control of consummatory behavior. The muscarinic cholinergic system is known to regulate membrane excitability and control low-frequency rhythmic activity in the mPFC. Muscarinic receptors (mAChRs) act through KCNQ (Kv7) potassium channels, which have recently been linked to the orexigenic peptide ghrelin. To understand if drugs that act on KCNQ channels within the mPFC have effects on consummatory behavior, we made infusions of several muscarinic drugs (scopolamine, oxotremorine, physostigmine), the KCNQ channel blocker XE-991, and ghrelin into the mPFC and evaluated their effects on consummatory behavior. A consistent finding across all drugs was an effect on the duration of licking bouts when animals consume solutions with a relatively high concentration of sucrose. The muscarinic antagonist scopolamine reduced bout durations, both systemically and intra-cortically. By contrast, the muscarinic agonist oxotremorine, the cholinesterase inhibitor physostigmine, the KCNQ channel blocker XE-991, and ghrelin all increased the durations of licking bouts when infused into the mPFC. Our findings suggest that cholinergic and ghrelinergic signaling in the mPFC, acting through KCNQ channels, regulates the expression of palatability.

The medial prefrontal cortex is crucial for the maintenance of persistent licking and the expression of incentive contrast.

We examined the role of the medial prefrontal cortex (mPFC) in reward processing and the control of consummatory behavior. Rats were trained in an operant licking procedure in which they received alternating access to solutions with relatively high and low levels of sucrose (20 and 4%, w/v). Each level of sucrose was available for fixed intervals of 30 s over 30 min test sessions. Over several days of training, rats came to lick persistently when the high level of sucrose was available and suppressed licking when the low level of sucrose was available. Pharmacological inactivations of the mPFC, specifically the rostral part of the prelimbic area, greatly reduced intake of the higher value fluid and only slightly increased intake of the lower value fluid. In addition, the inactivations altered within-session patterns and microstructural measures of licking. Rats licked equally for the high and low levels of sucrose at the beginning of the test sessions and "relearned" to reduce intake of the low value fluid over the test sessions. Durations of licking bouts (clusters of licks with inter-lick intervals <0.5 s) were reduced for the high value fluid and there were many more brief licking bouts (<1 s) when the low value fluid was available. These effects were verified using an alternative approach (optogenetic silencing using archaerhodopsin) and were distinct from inactivation of the ventral striatum, which simply increased overall intake. Our findings suggest that the mPFC is crucial for the maintenance of persistent licking and the expression of learned feeding strategies.

Mistakes were made: neural mechanisms for the adaptive control of action initiation by the medial prefrontal cortex.

Studies in rats, monkeys and humans have established that the medial prefrontal cortex is crucial for the ability to exert adaptive control over behavior. Here, we review studies on the role of the rat medial prefrontal cortex in adaptive control, with a focus on simple reaction time tasks that can be easily used across species and have clinical relevance. The performance of these tasks is associated with neural activity in the medial prefrontal cortex that reflects stimulus detection, action timing, and outcome monitoring. We describe rhythmic neural activity that occurs when animals initiate a temporally extended action. Such rhythmic activity is coterminous with major changes in population spike activity. Testing animals over a series of sessions with varying pre-stimulus intervals showed that the signals adapt to the current temporal demands of the task. Disruptions of rhythmic neural activity occur on error trials (premature responding) and lead to a persistent encoding of the error and a subsequent change in behavioral performance (i.e. post-error slowing). Analysis of simultaneously recorded spike activity suggests that the presence of strong theta rhythms is coterminous with altered network dynamics, and might serve as a mechanism for adaptive control. Computational modeling suggests that these signals may enable learning from errors. Together, our findings contribute to an emerging literature and provide a new perspective on the neuronal mechanisms for the adaptive control of action.