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. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes.

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. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information.

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. Average firing rate during recording sessions was higher during dDNMTP for neurons with event-related responses, but lower for neurons with activity unrelated to behavioural events. Thus, compared to SLP, dDNMTP appears to enhance the activity of neurons that represent behaviourally relevant information and to suppress the activity of neurons that do not. dDNMTP was associated with responses related to preparation and memory delay that were not observed during SLP as well as enhanced responses related to movement and reinforcement. These results provide evidence that choice in the dDNMTP task is associated with adaptive changes in background firing rates and coding properties of mPFC neurons.

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. Unilateral inactivation reduced normalized task-related responses in the ipsilateral mPFC without disrupting behavior needed to characterize event-related neuronal activity. Our results extend earlier findings that focused on delay-related activity by showing that central thalamic inactivation interferes with responses related to actions and outcomes that occur outside the period of memory delay. These findings are consistent with the broad effects of central thalamic lesions on behavioral measures of reinforcement-guided responding. Most (7/8) of the prefrontal response types affected by thalamic inactivation have also been observed in MD during dDNMTP. These results support the hypothesis that MD and IL act as transthalamic gates: monitoring prefrontal activity through corticothalamic inputs; integrating this information with signals from motivational and sensorimotor systems that converge in thalamus; and acting through thalamocortical projections to enhance expression of neuronal responses in the PFC that support adaptive goal-directed behavior.

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. Normalised population averages revealed a precisely timed cascade of population responses representing the temporal organisation behavioural events that constitute delayed non-matching to position trials. Firing field analyses identified a subset of neurons with restricted spatial fields: responding to the conjunction of a behavioural event with a specific location. Anatomical analyses showed considerable overlap in the distribution of different response types in medial prefrontal cortex with a significant trend for dorsal areas to contain more neurons with action-related activity and ventral areas more responses related to action outcomes. CONCLUSION: These results indicate that medial prefrontal cortex contains discrete populations of neurons that represent the temporal organisation of actions and outcomes during delayed non-matching to position trials. They support the hypothesis that medial prefrontal cortex promotes flexible control of complex behaviours by action-outcome contingencies.

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. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior.

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. Combined event-related and video tracking analyses revealed variability in spatial tuning of neurons with similar event-related activity. While all correlated neurons exhibited spatial tuning broadly consistent with relevant task events, for instance reinforcement-related activity concentrated in locations where reinforcement was delivered, some had elevated activity in more specific locations, for instance reinforcement-related activity in one of several locations where reinforcement was delivered. Timing analyses revealed a limited set of distinct response types with activity time-locked to critical behavioral events that represent the temporal organization of dDNMTP trials. Our results suggest that reinforcement-guided decision-making emerges from discrete populations of medial prefrontal neurons that encode information related to planned or ongoing movements and actions and anticipated or actual action-outcomes in conjunction with information about spatial context.

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. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task.

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. How should the thalamus be viewed in the context of the rest of the brain? Although its role extends well beyond relaying of sensory information from the periphery, the main function of many of its subdivisions does appear to be that of a relay station, transmitting neural signals primarily to the cerebral cortex from a number of brain areas. In cognition, its main contribution may thus be to coordinate signals between diverse regions of the telencephalon, including the neocortex, hippocampus, amygdala, and striatum. This central coordination is further subject to considerable extrinsic control, for example, inhibition from the basal ganglia, zona incerta, and pretectal regions, and chemical modulation from ascending neurotransmitter systems. What follows is a brief review on the role of the thalamus in aspects of cognition and behavior, focusing on a summary of the topics covered in a mini-symposium held at the Society for Neuroscience meeting, 2014.

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. VC-DNM is trained in automated radial mazes and requires rats to choose between two arms, randomly selected from eight alternatives on each trial. DNMTP is affected by hippocampal and mPFC lesions while VC-DNM is affected by hippocampal, but not mPFC lesions (Porter et al. (2000) Behav Brain Res 109:69-81). We found evidence of a localized (low dose) effect of ReRh inactivation on DNMTP but not VC-DNM. This was confirmed by comparison with muscimol injections in an anatomical control site. These results are consistent with evidence that Re and Rh affect measures of spatial working memory that depend on interactions between hippocampus and mPFC, but not measures that depend on hippocampus alone.

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. Drugs that increase activity have been found to enhance and impair memory depending on the dose tested. Electrical deep brain stimulation (DBS) similarly enhances working memory at low stimulating currents and impairs it at higher currents. These effects are time dependent. They were observed when DBS was applied during the memory delay (retention) or choice response (retrieval) but not earlier in trials during the sample (acquisition) phase. The effects of microinjected drugs and DBS are consistent with the Yerkes-Dodson law, which describes an inverted-U relationship between arousal and behavioral performance. Alternatively these results may reflect desensitization associated with higher levels of stimulation, spread of drugs or current to adjacent structures, or activation of less sensitive neurons or receptors at higher DBS currents or drug doses.

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. The effects of caudal intralaminar lesions were doubly dissociated from ReRh lesions, affecting VSRT, but not RAM or serial VSRT performance. Rostral intralaminar lesions did not produce significant impairments, other than a subgroup with larger lesions that were impaired performing a delayed RAM task. Combined lesions damaging all three sites produced RAM deficits comparable to ReRh lesions and VSRT deficits comparable to caudal intralaminar lesions. Thus there was no indication that deficits produced by lesions in one site were exacerbated significantly by the cumulative effect of damage in other parts of the midline-intralaminar complex. The effects of ReRh lesions provide evidence that these nuclei affect memory functions of hippocampus and medial prefrontal cortex. The double dissociation observed between the effects of ReRh and caudal intralaminar nuclei provides evidence that different nuclei within the midline-intralaminar complex affect distinct aspects of cognition consistent with the effects of lesions in the terminal fields they innervate.

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. Inhibiting activity with the GABA(A) agonist muscimol impaired DMTP. Decreasing GABA(A) tone with FG-7142 (N-methyl-beta-carboline-3-carboxamide) improved DMTP at low but not high doses. Orexin A, which depolarizes thalamocortical neurons locally within the ILn, improved DMTP, whereas the cholinergic agonist carbachol impaired performance at the highest dose tested. These drug effects were unaffected by partial mPF lesions in a subset of animals. Microinjection results are consistent with an inverted-U relationship between thalamic activity and DMTP. This relationship was confirmed by event-related electrical stimulation, which produced improvement at low stimulation currents and impairment at higher currents. Electrical stimulation affected DMTP when applied at the start of the memory delay or choice response, but not earlier when trials began or the sample lever was presented. Our results are consistent with evidence that the rostral ILn play a role in retrieval, carrying response-related information across brief memory delays and facilitating memory-guided responding. They also provide evidence that treatments stimulating rostral ILn activity may be an effective means to enhance working memory and related cognitive processes and thus to treat disorders that affect these functions.

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 (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABA(A) agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 micromol/kg) and scopolamine (0.03, 0.09, 0.26 micromol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3-s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention-demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors.

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. repeated) of nose-pokes in a response. Learning was studied by comparing sessions with random or repeated cues. All cortical lesions increased reaction time (RT) during response initiation. These effects were larger for nose-pokes initiating sequential responses but spared RT for nose-pokes completing them. Repetition learning had significant effects on the speed and accuracy of single nose-poke responses that were unaffected by any of the cortical lesions. Repetition learning had more complex effects on sequential responding. RTs increased for nose-pokes initiating sequences over several sessions of continuous repetition and then decreased or leveled off. RTs decreased incrementally across all repetition sessions for subsequent nose-pokes in repeated sequences, following a time-course consistent with habit learning. Lesions involving M2 and MFr cortex exacerbated the increase in RT during initiation without affecting the incremental decrease in RT for nose-pokes completing repeated sequences. These results were confirmed by analyses of interference effects when training shifted from repeated (learned) to random (novel) sequences or to a new repeated sequence. These results implicate dorsomedial frontal cortex in organizational aspects of sensory-guided responding and motor sequence learning reflected in RT during response initiation.

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. When sequences were repeated, response time (RT) increased for nose pokes initiating the sequence and decreased for nose pokes completing it. These effects developed incrementally across sessions, consistent with the time course of habit learning. Medial (mCPu), lateral, and complete (CPu) caudate-putamen lesions affected speed and accuracy of single nose poke responses, confirming the role of these areas in guiding responses with external sensory stimuli. None of these lesions affected the short-term increase in accuracy observed when single nose poke responses were repeated. Both mCPu and CPu lesions increased RTs for initiating sequential responses, effects that were exacerbated across sessions in which specific sequences were repeated. None of the lesions affected the gradual decrease in RT for nose pokes completing repeated sequences. Correlational analyses confirmed the relationship between the extent of dorsal striatal damage and the ability to respond to brief luminance cues and to initiate learned sequences. These results provide evidence implicating dorsal striatum in higher-level organizational aspects of learning reflected in planning that precedes the execution of learned action sequences.

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. METHODS: Rats were trained to criterion for one of three tasks: visuospatial reaction time (VSRT), a measure of attention sensitive to PFC lesions, delayed matching trained with retractable levers (DM-RL), and delayed nonmatching trained in radial mazes (DNM-RM), measures of spatial working memory sensitive to PFC and hippocampal lesions, respectively. LC activity was manipulated with bilateral 0.5-microl injections of the alpha-2 agonist clonidine (0, 1.1, 4.5, and 18 nmol). RESULTS: Clonidine produced significant dose-dependent impairments of VSRT, affecting choice response time at the 18-nmol dose and choice accuracy at the 4.5- and 18-nmol doses. Clonidine had no effect on DMRL or DNM-RM at any of the doses tested. CONCLUSIONS: Reversible reduction of LC-NE activity by clonidine impaired measures of visuospatial attention sensitive to PFC lesions but were insufficient to affect PFC- or hippocampal-dependent measures of spatial working memory. These results are consistent with reports that LC-NE lesions produce chronic deficits in attention with little or no effect on measures of working memory.

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. The 2nd study demonstrated dose-dependent DMRL impairment following microinjection of gamma-aminobutyric acidA, glutamate, or mu-opioid agonists in VP. In the 3rd study, VP lesions had no effect on varying choice radial-maze delayed nonmatching, a measure sensitive to hippocampal (but not prefrontal) lesions. These results suggest a common role in spatial memory for VP and other components of prefrontal-ventral striatopallidothalamic circuits distinct from hippocampal function.

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. The effects of M/IL and VM lesions were delay independent. Even when combined, these lesions had no effect on varying choice radial maze delayed nonmatching, a task sensitive to hippocampal or anterior thalamic (but not prefrontal) lesions. These results demonstrate effects of MD, M/IL, and VM lesions distinct from the contributions of hippocampus or anterior thalamus to spatial memory.

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. Results showed comparable impairments for AT and PH lesions that added without interaction in the combined AT-PH group. During chronic recovery, the AT-PH group exhibited delay-dependent deficits comparable to previous results for hippocampal lesions. Thus, AT and PH lesions appear to have separate effects that together disrupt hippocampus-dependent spatial memory.