Where Actions Meet Outcomes: Medial Prefrontal Cortex, Central Thalamus, and the Basal Ganglia.

Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia.

Central Thalamic-Medial Prefrontal Control of Adaptive Responding in the Rat: Many Players in the Chamber.

The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC.

Effects of choice on neuronal activity in anterior cingulate, prelimbic, and infralimbic cortices in the rat: Comparison of serial lever pressing with delayed nonmatching to position.

The ability to choose between response alternatives based on their likely consequences depends on distributed neural circuits that involve rodent medial prefrontal cortex (mPFC). To understand the effects of choice on mPFC function, we compared the activity of mPFC neurons in rats performing two tasks: dynamic delayed nonmatching to position (dDNMTP), a task with a prefrontal-dependent conditional choice, and serial lever pressing (SLP), a task lacking a choice but trained in the same apparatus with sequences of actions and reinforcements matched to dDNMTP. More neurons exhibited event-related responses during dDNMTP than SLP.

Central thalamic inactivation impairs the expression of action- and outcome-related responses of medial prefrontal cortex neurons in the rat.

The mediodorsal (MD) and adjacent intralaminar (IL) and midline nuclei provide the main thalamic input to the medial prefrontal cortex (mPFC) and are critical for associative learning and decision-making. MD neurons exhibit activity related to actions and outcomes that mirror responses of mPFC neurons in rats during dynamic delayed non-match to position (dDNMTP), a variation of DNMTP where start location is varied randomly within an open octagonal arena to avoid confounding behavioral events with spatial location. To test whether the thalamus affects the expression of these responses in mPFC, we inhibited the central thalamus unilaterally by microinjecting muscimol at doses and sites found to affect decision-making when applied bilaterally.

Representation of actions and outcomes in medial prefrontal cortex during delayed conditional decision-making: Population analyses of single neuron activity.

Background: To respond adaptively in a dynamic environment, it is important for organisms to utilise information about recent events to decide between response options.

Methods: To examine the role of medial prefrontal cortex in adaptive decision-making, we recorded single neuron activity in rats performing a dynamic delayed non-matching to position task.

Results: We recorded activity from 1335 isolated neurons, 458 (34%) with criterion event-related activity, of which 431 (94%) exhibited 1 of 10 distinct excitatory response types: five at different times relative to delivery (or lack) of reinforcement following sample and choice responses and five correlated with movements or lever press actions that occurred multiple times in each trial.

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task.

The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making.

Prefrontal Neurons Encode Actions and Outcomes in Conjunction with Spatial Location in Rats Performing a Dynamic Delayed Non-Match to Position Task.

To respond adaptively to change organisms must utilize information about recent events and environmental context to select actions that are likely to produce favorable outcomes. We developed a dynamic delayed nonmatching to position task to study the influence of spatial context on event-related activity of medial prefrontal cortex neurons during reinforcement-guided decision-making. We found neurons with responses related to preparation, movement, lever press responses, reinforcement, and memory delays.

The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination.

Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination.

Advances in understanding mechanisms of thalamic relays in cognition and behavior.

The main impetus for a mini-symposium on corticothalamic interrelationships was the recent number of studies highlighting the role of the thalamus in aspects of cognition beyond sensory processing. The thalamus contributes to a range of basic cognitive behaviors that include learning and memory, inhibitory control, decision-making, and the control of visual orienting responses. Its functions are deeply intertwined with those of the better studied cortex, although the principles governing its coordination with the cortex remain opaque, particularly in higher-level aspects of cognition.

Cognitive activation by central thalamic stimulation: the yerkes-dodson law revisited.

Central thalamus regulates forebrain arousal, influencing activity in distributed neural networks that give rise to organized actions during alert, wakeful states. Central thalamus has been implicated in working memory by the effects of lesions and microinjected drugs in this part of the brain. Lesions and drugs that inhibit neural activity have been found to impair working memory.

Inactivation of ventral midline thalamus produces selective spatial delayed conditional discrimination impairment in the rat.

The reuniens (Re) and rhomboid (Rh) nuclei are organized to influence activity in distributed limbic networks involving hippocampus and medial prefrontal cortex (mPFC). To elucidate the role of these nuclei in spatial memory we inactivated Re and Rh in rats with the GABA(A) agonist muscimol and compared effects on two spatial delayed conditional discriminations: delayed nonmatching to position (DNMTP) and varying choice radial maze delayed nonmatching (VC-DNM). DNMTP is trained in operant chambers and requires rats to choose between the same two levers on all trials.

Lesions of reuniens and rhomboid thalamic nuclei impair radial maze win-shift performance.

The reuniens (Re) and rhomboid (Rh) nuclei are major sources of thalamic input to hippocampus and medial prefrontal cortex. We compared effects of lesions in ReRh and other parts of the midline-intralaminar complex on tasks affected by lesions in terminal fields innervated by these nuclei, including: visuospatial reaction time (VSRT), a measure of sensory guided responding; serial VSRT, a measure of action sequence learning; and win/shift radial arm maze (RAM) measures of spatial memory. ReRh lesions affected RAM, but not VSRT or serial VSRT performance.

Memory enhancement with event-related stimulation of the rostral intralaminar thalamic nuclei.

The rostral intralaminar thalamic nuclei (ILn) are organized to activate pathways originating in medial prefrontal cortex (mPF) that mediate memory-guided responding during alert, wakeful states. Previous studies have shown that rostral ILn or mPF lesions produce deficits in delayed matching to position (DMTP). Here, we manipulated rostral ILn activity in rats by microinjecting drugs or applying electrical current and examined effects on DMTP.

Cholinergic modulation of visuospatial responding in central thalamus.

Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory-guided goal-directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.

Effects of frontal cortex lesions on action sequence learning in the rat.

To understand the role of frontal cortex in motor sequence learning we compared the effects of motor (M1), premotor (M2) and midline frontal (MFr) cortical lesions on rats making nose-pokes guided by luminance cues. Organizational demands were manipulated by varying the number (1 vs. 5) and predictability (random vs.

The role of striatum in initiation and execution of learned action sequences in rats.

To understand the role of striatum in motor sequence learning, we trained rats to perform a series of tasks measuring speed and accuracy of responding to luminance cues presented as discriminative stimuli for single nose pokes or for sequences of nose pokes in a serial reaction time task. Habit (stimulus-response) learning was measured by comparing performances when stimuli were repeated (predictable) with when they were selected randomly (unpredictable). Sequences had defined start and end points and were limited to five nose pokes to minimize chunking.

Lesions of specific and nonspecific thalamic nuclei affect prefrontal cortex-dependent aspects of spatial working memory.

Three studies compared lesions of specific mediodorsal (MD) and nonspecific midline/intralaminar (M/IL) and ventromedial (VM) thalamic nuclei placed to spare the anterior nuclei. Lesions of MD, M/IL, or VM impaired delayed matching trained with retractable levers, a measure of spatial memory affected by prefrontal cortical lesions. The effects of the MD lesion increased at longer retention intervals and thus appeared delay dependent.

Involvement of ventral pallidum in prefrontal cortex-dependent aspects of spatial working memory.

Ventral pallidum (VP) is an important source of limbic input to medial thalamus. Three studies examined the role of VP in spatial memory tasks impaired by medial thalamic lesions. In the 1st study, rats with VP lesions were impaired performing delayed matching trained with retractable levers (DMRL), a measure sensitive to prefrontal (but not hippocampal) damage.

Effects of clonidine in the locus coeruleus on prefrontal- and hippocampal-dependent measures of attention and memory in the rat.

Rationale: The locus coeruleus (LC) is the source of norepinephrine (NE) in the prefrontal cortex (PFC) and hippocampus and may influence cognitive functions of these areas. Chronic effects of LC-NE lesions do not correspond consistently with acute effects of systemic or intracortical injections of adrenergic agents.

Objective: These studies aim to manipulate LC activity pharmacologically and study acute effects on measures of attention and memory that depend on the PFC and hippocampus.

Impairment of radial maze delayed nonmatching after lesions of anterior thalamus and parahippocampal cortex.

This study compared the effects of lesions damaging hippocampus-related pathways in anterior thalamus (AT) and parahippocampal (PH) cortex on allocentric spatial memory. Rats were trained to perform radial maze delayed nonmatching (DNM) with random selection of arms to prevent egocentric solutions. After experimental treatment (control, excitotoxic AT, radiofrequency PH, or combined AT-PH lesions), rats were retrained for 30 sessions from 2 to 8 weeks after surgery.

A double dissociation within striatum between serial reaction time and radial maze delayed nonmatching performance in rats.

Lesions involving the intralaminar thalamic nuclei have been associated with impairments in working memory and intentional motor function in human clinical cases and animal models of amnesia. The intralaminar nuclei have afferent and efferent connections related to striatum. To test whether disruption of striatal function can account for impairments produced by intralaminar lesions, we investigated the effects of striatal lesions on two tasks known to be impaired by intralaminar damage in the rat: radial maze delayed nonmatching (DNM), a measure of spatial working memory, and self-paced serial reaction time (SRT), a measure of intentional response speed.