Search

Psychostimulant exposure alters the activity of ventral pallidum (VP) projection-neurons. However, the molecular underpinnings of these circuit dysfunctions are unclear. We used RNA- sequencing to reveal alterations in the transcriptional landscape of the VP that are induced by cocaine self-administration in mice. We then probed gene expression in select VP neuronal subpopulations to isolate a circuit associated with cocaine intake. Finally, we used both overexpression and CRISPR-mediated knockdown to test the role of a gene target on cocaine- mediated behaviors as well as dendritic spine density. Our results showed that a large proportion (55%) of genes associated with structural plasticity were changed 24 hours following cocaine intake. Among them, the transcription factor Nr4a1 (Nuclear receptor subfamily 4, group A, member 1, or Nur77) showed high expression levels. We found that the VP to mediodorsal thalamus (VP→MDT) projection neurons specifically were recapitulating this increase in Nr4a1 expression. Overexpressing Nr4a1 in VP→MDT neurons enhanced drug-seeking and drug- induced reinstatement, while Nr4a1 knock down prevented self-administration acquisition and subsequent cocaine-mediated behaviors. Moreover, we showed that Nr4a1 negatively regulated spine dynamics in this specific cell subpopulation. Together, our study identifies for the first time the transcriptional mechanisms occurring in VP in drug exposure. Our study provides further understanding on the role of Nr4a1 in cocaine-related behaviors and identifies the crucial role of the VP→MDT circuit in drug intake and relapse-like behaviors.

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al., 2012) and used linear multielectrode arrays to record neural activity in the MD and PFC simultaneously. We found that the two structures made clearly different contributions to distributed processing for cognitive control: MD neurons were specialized for decision-making and response selection, whereas prefrontal neurons were specialized to preferentially encode the environmental state on which the decision was based. In addition, we observed that functional coupling between MD and PFC was strongest when the decision as to which of the two responses in the task to execute was being made. These findings delineate unique contributions of MD and PFC to distributed processing for cognitive control and characterized neural dynamics in this network associated with normative cognitive control performance.

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas.

Predicting when future events will occur and adjusting behavior accordingly is critical to adaptive behavior. Despite this, little is known about the brain networks that encode time and how this ultimately impacts decision-making. One established finding is that the prefrontal cortex (PFC) and its non-human analogues (e.g., the rodent prelimbic cortex; PL) mediate timing. This provides a starting point for exploring the networks that support temporal processing by identifying areas that interact with the PFC during timing tasks. For example, substantial work has explored the role of frontostriatal circuits in timing. However, other areas are undoubtedly involved. The mediodorsal nucleus of the thalamus (MD) is an excellent candidate region. It shares dense, reciprocal connections with PFC-areas in both humans and non-human species and is implicated in cognition. However, causal data implicating MD-PFC interactions in cognition broadly is still sparse, and their role in timing specifically is currently unknown. To address this, we trained male rats on a time-based, decision-making task referred to as the ‘peak-inter- val’ procedure. During the task, presentation of a cue instructed the rats to respond after a specific interval of time elapsed (e.g., tone-8 seconds). We incorporated two cues; each requiring a response after a distinct time-interval (e.g., tone-8 seconds / light-16 seconds). We tested the effects of either reversibly inactivating the MD or PL individually or functionally disconnecting them on performance. All manipulations caused a comparable timing deficit. Specifically, responses showed little organization in time, as if primarily guided by motivational systems. These data expand our understanding of the networks that support timing and suggest that MD-PL interactions specifically are a core component. More broadly, our results suggest that timing tasks provide a reliable assay for characterizing the role of MD-PL interactions in cognition using rodents, which has been difficult to establish in the past.

At the heart of the prefrontal executive and limbic networks is the mediodorsal thalamus (MD). Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, virtually nothing is known about the physiology of neurons in MD. Here, we injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult (8 – 12 week old) male and female wildtype mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD→mPFC neurons). MD→mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. We found that that MD-M→mPFC neurons have longer membrane time constants, higher membrane resistance, less Hyperpolarization and Cyclic Nucleotide gated (HCN) channel activity, and more readily generate action potentials compared to MD-L→mPFC neurons. Additionally, MD-M→mPFC neurons have larger and more complex dendritic arbors compared to MD-L→mPFC neurons. These data demonstrating that the two populations of MD→mPFC neurons have distinct physiologies and morphologies suggests a differential role in thalamocortical information processing and potentially behavior.

The ability to represent time in the brain relies on network interactions across multiple brain areas. While much attention has been paid to the role of prefrontal cortex and basal ganglia in timing, little work has been aimed towards understanding the role of the thalamus in timing. To this end, we utilized pharmacological and optogenetic techniques in mice to test the role of the mediodorsal nucleus of the thalamus (MD) in interval timing. The MD is strongly connected with the prefrontal cortex and receives major inputs from the basal ganglia output nuclei. We used an operant temporal production task, in which mice indicate their expected timing of available rewards by pressing a lever in anticipation. On probe trials, inactivation of the MD with muscimol produced rightward shifts in peak pressing as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD resulted in similar changes in timing; the shift in peak time is proportional to the duration of inhibition. The observed effects were found to be independent of significant changes in movement. Taken together, these findings provide strong evidence for the importance of thalamo-cortical projections in maintaining proper timing behavior. Significance Statement While extensive research has been dedicated to the involvement of the prefrontal cortex in interval timing behavior, the degree to which thalamic inputs contribute to timing is unclear. Using pharmacological and optogenetic inhibition of the MD, a prefrontal projecting thalamic nucleus, we demonstrate a key role of this thalamic nucleus in timing behavior.

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.

The focus of this literature review is on the three interacting brain areas that participate in decision‐making: basal ganglia, ventral motor thalamic nuclei, and medial prefrontal cortex, with an emphasis on the participation of the ventromedial and ventral anterior motor thalamic nuclei in prefrontal cortical function. Apart from a defining input from the mediodorsal thalamus, the prefrontal cortex receives inputs from ventral motor thalamic nuclei that combine to mediate typical prefrontal functions such as associative learning, action selection, and decision‐making. Motor, somatosensory and medial prefrontal cortices are mainly contacted in layer 1 by the ventral motor thalamic nuclei and in layer 3 by thalamocortical input from mediodorsal thalamus. We will review anatomical, electrophysiological, and behavioral evidence for the proposed participation of ventral motor thalamic nuclei and medial prefrontal cortex in rat and mouse motor decision‐making.

Interactions between the prefrontal cortex (PFC) and mediodorsal thalamus are critical for cognitive flexibility, yet the underlying computations are unknown. To investigate frontothalamic substrates of cognitive flexibility, we developed a behavioral task in which mice switched between different sets of learned cues that guided attention toward either visual or auditory targets. We found that PFC responses reflected both the individual cues and their meaning as task rules, indicating a hierarchical cue-to-rule transformation. Conversely, mediodorsal thalamus responses reflected the statistical regularity of cue presentation and were required for switching between such experimentally specified cueing contexts. A subset of these thalamic responses sustained context-relevant PFC representations, while another suppressed the context-irrelevant ones. Through modeling and experimental validation, we find that thalamic-mediated suppression may not only reduce PFC representational interference but could also preserve unused cortical traces for future use. Overall, our study provides a computational foundation for thalamic engagement in cognitive flexibility.

Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains, such as working memory and behavioral flexibility, have classically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders.

Hyperexcitability of the anterior cingulate cortex (ACC) is thought to drive aversion associated with chronic neuropathic pain. Here we studied the contribution of input from mediodorsal thalamus (MD) to ACC, using sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited pain-related aversion in both models. Unexpectedly, excitatory responses of layer V ACC neurons to MD inputs were significantly weaker in pain models compared to controls. This caused the ratio between excitation and feedforward inhibition elicited by MD input to shift towards inhibition, specifically for subcortically-projecting (SC) layer V neurons. Furthermore, direct inhibition of SC neurons reproduced the pain-related aversion elicited by activating MD inputs. Finally, both the ability to elicit pain-related aversion, and the decrease in excitation, were specific to MD inputs; activating basolateral amygdala inputs produced opposite effects. Thus, chronic pain-related aversion may reflect activity changes in specific pathways, rather than generalized ACC hyperactivity.

Objective The objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. Methods Multiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. Results There were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking − 0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. Conclusions Both the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity.

Emotional contagion, a primary form of empathy, is present in rodents. Among emotional contagion behaviors, social transmission of fear is the most studied. Here, we modified a paradigm used in previous studies to more robustly assess the social transmission of fear in rats that experienced foot-shock. We used resting-state functional magnetic resonance imaging to show that foot-shock experience enhances the regional connectivity of the anterior cingulate cortex (ACC). We found that lesioning the ACC specifically attenuated the vicarious freezing behavior of foot-shock-experienced observer rats. Furthermore, ablation of projections from the ACC to the mediodorsal thalamus (MDL) bilaterally delayed the vicarious freezing responses, and activation of these projections decreased the vicarious freezing responses. Overall, our results demonstrate that, in rats, the ACC modulates vicarious freezing behavior via a projection to the MDL and provide clues to understanding the mechanisms underlying empathic behavior in humans.

Both the medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety, however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency (4–12 Hz) mPFC activity, and also reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function including anxiety-related behaviors.

The mediodorsal nucleus (MD) represents just one piece of a complex relay structure situated within the brain, called the thalamus. MD is characterized by its robust interconnections with other brain areas, especially with limbic-related structures. Given the close anatomo-functional relationship between the MD and the limbic system, this particular thalamic nucleus can directly influence various affective behaviors and participate in cognition. In this work, we review data collected from multiple anatomical studies conducted in rodent, human, and non-human primates, highlighting the complexity of this structure and of the neural networks in which it takes part. We provide proof that the MD is involved in the unification of several anatomical structures, being able to process the information and influence the activity in numerous cortical and subcortical neural circuits. Moreover, we uncover intrinsic and extrinsic mechanisms that offer MD the possibility to execute and control specific high functions of the nervous system. The collected data indicate the great importance of the MD in the limbic system and offer relevant insight into the organization of thalamic circuits that support MD functions.

Methamphetamine (MA) and other psychostimulants target the motive circuit of the brain, which is involved in reward, behavioral sensitization, and relapse to drug-seeking/taking behavior. In spite of this fact, the data regarding the effective connectivity (EC) in this circuit among MA users is scarce. The present study aimed to assess resting-state EC in the motive circuit of MA users during abstinence using the fMRI technique. Seventeen MA users after abstinence and 18 normal controls were examined using a 3 T Siemens fMRI scanner. After extracting time series of the motive circuit, EC differences in the motive circuit were analyzed using dynamic causal modeling (DCM). The findings revealed that abstinent MA users had an enhanced EC from the prefrontal cortex (PFC) to the ventral palladium (VP) (PFC→VP) and on the mediodorsal thalamus (MD) self-loop (MD→MD), but they showed a decreased connectivity on the VP self-loop (VP→VP) compared to healthy controls. The findings suggest that abstinent MA users may suffer from a limited pathology in connectivity within the motive circuit involved in reward, behavioral sensitization, and relapse. The enhanced PFC→VP seems to be a compensatory mechanism to control or regulate the subcortical regions involved in reward and behavioral sensitization. Furthermore, the enhanced connectivity on the MD self-loop and the decreased connectivity on the VP self-loop in abstinent MA users may, at least partially, affect the output of the limbic system, which can be seen in the behavioral sensitization and relapse processes. Nonetheless, further investigation in this area is strongly recommended to elucidate the exact mechanisms involved.

The neural basis of memory is highly distributed, but the thalamus is known to play a particularly critical role. However, exactly how the different thalamic nuclei contribute to different kinds of memory is unclear. Moreover, whether thalamic connectivity with the medial temporal lobe (MTL), arguably the most fundamental memory structure, is critical for memory, remains unknown. We explore these questions using an fMRI recognition memory paradigm that taps familiarity and recollection (i.e., the two types of memory that support recognition) for objects, faces and scenes. We show that the mediodorsal thalamus (MDt) plays a material-general role in familiarity, while the anterior thalamus plays a material-general role in recollection. Material-specific regions were found for scene familiarity (ventral posteromedial and pulvinar thalamic nuclei) and face familiarity (left ventrolateral thalamus). Increased functional connectivity between the MDt and the parahippocampal (PHC) and perirhinal cortices (PRC) of the MTL underpinned increases in reported familiarity confidence. The extent of this connectivity reliably correlated with familiarity performance depending on the type of stimulus in memory. MDt-PRC connectivity correlated with object and face familiarity, while MDt-PHC connectivity correlated with scene familiarity. These findings suggest that familiarity signals are generated through the dynamic interaction of functionally connected MTL-thalamic structures.

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed “task engagement,” may enable context-dependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision-making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4–7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.SIGNIFICANCE STATEMENTWhen rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated compared with task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex and thus represents a form of “top-down” regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task-dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing.

A recent focus of addiction research has been on the effect of drug exposure on the neural processes that mediate the acquisition and performance of goal-directed instrumental actions. Deficits in goal-directed control and a consequent dysregulation of habit learning processes have been described as resulting in compulsive drug seeking. Similarly, considerable research has focussed on the motivational and emotional changes that drugs produce and that result in changes in the incentive processes that modulate goal-directed performance. Although these areas have developed independently, we argue that the effects they described are likely not independent. Here we hypothesize that these changes result from a core deficit in the way the learning and performance factors that support goal-directed action are integrated at a neural level to maintain behavioural control. A dorsal basal ganglia stream mediating goal-directed learning and a ventral stream mediating various performance factors find several points of integration in the cortical basal ganglia system, most notably in the thalamocortical network linking basal ganglia output to a variety of cortical control centres. Recent research in humans and other animals is reviewed suggesting that learning and performance factors are integrated in a network centred on the mediodorsal thalamus and that disintegration in this network may provide the basis for a 'switch' from recreational to dysregulated drug seeking resulting in the well documented changes associated with addiction.

The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia.

Identifying the neurocognitive mechanisms that lead individuals remembering to execute an intention at the right moment (prospective memory, PM) and how such mechanisms are influenced by the features of that intention is a fundamental theoretical challenge. In particular, the functional contribution of subcortical regions to PM is still unknown. This study was aimed at investigating the role of the medial subdivision of the mediodorsal thalamic nucleus (mMDT) in PM, with particular focus on the processes that are mediated by the projections from/to this structure. We analysed the performance of a patient (OG) with a right-sided lesion involving the mMDT in a series of PM tasks that varied for focality (i.e., overlapping of processes for the PM and ongoing tasks) and emotional valence of the stimuli, comparing the patient's performance with that of a control group. We found that the mMDT damage led to deficits in PM that were modulated by focality and emotional valence. OG indeed showed: a greater cost in the ongoing performance when a non-focal PM task was added; a slowing down in retrieving the intentions, in particular when these were associated with focal PM cues; an abnormal performance in the task with positive PM cues. Our findings provide evidence of a contribution of mMDT to PM and suggest a modulation of prefrontal-dependent strategic monitoring and a possible interaction with the limbic structures in the integration of emotion and PM processes. They also give support to the still controversial idea that connections with the perirhinal cortex mediate familiarity-based recognition.

Thalamus is a key crossroad structure involved in various functions relative to visual, auditory, gustatory, and somatosensory senses. Because of the specific organization of the olfactory pathway (i.e., no direct thalamic relay between sensory neurons and primary cortex), relatively little attention has been directed toward the thalamus in olfaction. However, an olfactory thalamus exists: the mediodorsal nucleus of the thalamus (MDT) receives input from various olfactory structures including the piriform cortex. How the MDT contributes to olfactory perception remains unanswered. The present study is a first step to gain insight into the function of the MDT in olfactory processing. Spontaneous and odor-evoked activities were recorded in both the MDT (single unit and local field potential) and the piriform cortex (local field potential) of urethane-anesthetized rats. We demonstrate that: 1) odorant presentation induces a conjoint, coherent emergence of beta-frequency-band oscillations in both the MDT and the piriform cortex; 2) 51% of MDT single units were odor-responsive with narrow-tuning characteristics across an odorant set, which included biological, monomolecular, and mixture stimuli. In fact, a majority of MDT units responded to only one odor within the set; 3) the MDT and the piriform cortex showed tightly related activities with, for example, nearly 20% of MDT firing in phase with piriform cortical beta-frequency oscillations; and 4) MDT-piriform cortex coherence was state-dependent with enhanced coupling during slow-wave activity. These data are discussed in the context of the hypothesized role of MDT in olfactory perception and attention.

Background Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural magnetic resonance imaging (MRI) studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through meta-analytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. Methods We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structural–functional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural–functional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insula’s task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum’s interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Conclusions Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). Electronic supplementary material The online version of this article (doi:10.1186/s12993-016-0100-5) contains supplementary material, which is available to authorized users.

Although it has been shown that the basolateral amygdala (BLA) and the mediodorsal thalamus (MD) are critical for goal-directed instrumental performance, much remains unknown about the respective contributions of these structures to action selection. The current study assessed the effects of post-training BLA and MD lesions on several tests of instrumental action selection. We found that MD damage disrupted the influence of pavlovian cues over action selection but left intact rats' ability to select actions based on either the expected value or the discriminative stimulus properties of the outcome. In contrast, BLA lesions impaired performance on all three tests of action selection. Because both lesion types disrupted the influence of cues that signal reward over instrumental performance, we then investigated the involvement of these structures in pavlovian contingency learning using a task in which the predictive status of one of two cues is degraded by delivering its outcome noncontingently during the intertrial interval. As expected, the sham group selectively suppressed their conditioned approach performance to the cue that no longer signaled its outcome but continued to respond to the control stimulus. In contrast, both lesioned groups were impaired on this task. Interestingly, whereas the MD group displayed a nonspecific reduction in responding to both cues, the BLA group continued to show high levels of responding to both cues as if their performance was completely insensitive to this contingency manipulation. These findings demonstrate that the BLA and MD make important yet distinct contributions to instrumental action selection.

Six experiments were performed to determine the role of mediodorsal thalamus (MD) in the devaluation task, varying the type of contingencies (Pavlovian or operant), the number of reinforcers (one versus two) and the order of experiments (in naïve or experimentally experienced rats). MD lesioned rats were impaired in devaluation performance when switched between Pavlovian and operant devaluation tasks, but not when switched from one Pavlovian devaluation task to another Pavlovian devaluation task. MD lesions caused no devaluation impairment in a multiple reinforcer Pavlovian devaluation task. These results suggest that MD lesions impair performance in devaluation tasks as a result of an inability to switch the form of associations made from one type of outcome-encoding association to another. This is in accord with previous literature suggesting that MD is needed for strategy set shifting. The results further suggest that MD is a necessary part of devaluation circuits only in cases in which previous associations need to be suppressed in order for new associations to be learned and control behavior, and otherwise the devaluation circuit does not require MD.

Highlights • Early insult of the mediodorsal thalamus (MD) disturbed cognitive behaviors. • Early MD damage decreased locomotor activity, and reduced social interactions. • Early insult of the MD disturbed postnatal maturation of affective behavior. • The MD is important for prefrontal cortex function during brain maturation., Early insults to the thalamus result in functional and/or structural abnormalities in the cerebral cortex. However, differences in behavioral and cognitive changes after early insult are not well characterized. The present study assessed whether early postnatal damage to mediodorsal nucleus of the thalamus (MD), reciprocally interconnected with the prefrontal cortex, causes behavioral and cognitive alterations in young adult rats. Rat pups at postnatal day 4 received bilateral electrolytic lesion of MD, or a MD Sham lesion or were anesthetized controls; on recovery they were returned to their mothers until weaning. Seven weeks later, all rats were tested with the following behavioral and cognitive paradigms: T-maze test, open field test, actimetry, elevated plus maze test, social interactions test and passive avoidance test. Rats with bilateral MD damage presented with disrupted recognition memory, deficits in shifting response rules, significant hypoactivity, increased anxiety-like behavior, deficits in learning associations as well as decreased locomotor activity, and reduced social interactions compared to MD Sham lesion and anesthetized Control rats. The lesion also caused significant decreases in pyramidal cell density in three frontal cortex regions: medial infralimbic cortex, dorsolateral anterior cortex, and cingulate Cg1 cortex. The present findings suggest a functional role for MD in the postnatal maturation of affective behavior. Further some of the behavioral and cognitive alterations observed in these young adult rats after early MD lesion are reminiscent of those present in major psycho-affective disorders, such as schizophrenia in humans.

Outcome-specific Pavlovian-instrumental transfer (PIT) demonstrates the way that reward-related cues influence choice between instrumental actions. The nucleus accumbens shell (NAc-S) contributes critically to this effect, particularly through its output to the rostral medial ventral pallidum (VP-m). Using rats, we investigated in two experiments the role in the PIT effect of the two major outputs of this VP-m region innervated by the NAc-S, the mediodorsal thalamus (MD) and the ventral tegmental area (VTA). First, two retrograde tracers were injected into the MD and VTA to compare the neuronal activity of the two populations of projection neurons in the VP-m during PIT relative to controls. Second, the functional role of the connection between the VP-m and the MD or VTA was assessed using asymmetrical pharmacological manipulations before a PIT test. It was found that, whereas neurons in the VP-m projecting to the MD showed significantly more neuronal activation during PIT than those projecting to the VTA, neuronal activation of these latter neurons correlated with the size of the PIT effect. Disconnection of the two pathways during PIT also revealed different deficits in performance: disrupting the VP-m to MD pathway removed the response biasing effects of reward-related cues, whereas disrupting the VP-m to VTA pathway preserved the response bias but altered the overall rate of responding. The current results therefore suggest that the VP-m exerts distinct effects on the VTA and MD and that these latter structures mediate the motivational and cognitive components of specific PIT, respectively.

The thalamus, once viewed as passively relaying sensory information to the cerebral cortex, is becoming increasingly acknowledged as actively regulating the information transmitted to cortical areas. There are a number of reasons for this change. First, evidence suggests that first-order thalamic areas, like the lateral geniculate nucleus, ventral division of the medial geniculate nucleus, and the ventral posterior nuclei, can modulate neural processing along the sensory pathways to the cortex according to behavioral context (O'Connor et al., 2002; McAlonan et al., 2008). Second, much of the thalamus receives relatively little input from the sensory periphery, instead receiving its major driving input from the cortex. This higher-order thalamus forms pathways between cortical areas, which can strongly influence cortical activity (Theyel et al., 2010; Purushothaman et al., 2012; Saalmann et al., 2012). Third, lesions to higher-order thalamic areas, such as the pulvinar and mediodorsal nucleus, can produce severe attention and memory deficits (Saalmann and Kastner, 2011; Baxter, 2013; Bradfield et al., 2013; Jankowski et al., 2013; Mitchell and Chakraborty, 2013), suggesting an important role for the thalamus in cognition. In this Research Topic, we bring together neuroscientists who study different parts of the thalamus, particularly the higher-order thalamic nuclei, to highlight thalamic contributions to learning (Bradfield et al., 2013; Habib et al., 2013), memory processes (Baxter, 2013; Funahashi, 2013; Jankowski et al., 2013; Mitchell and Chakraborty, 2013; Saalmann, 2014), set-shifting (Bradfield et al., 2013; Minamimoto et al., 2014; Saalmann, 2014), language (Klostermann et al., 2013), as well as movement monitoring and control (Ostendorf et al., 2013; Prevosto and Sommer, 2013; Minamimoto et al., 2014). These studies incorporate a range of methods, from molecular to systems-level approaches, and connect rodent, non-human primate and human data, for a better understanding of human cognition. The first three articles focus on movement monitoring and motor control. Based on lesion data from clinical subjects, Ostendorf et al. (2013) show that the central thalamus makes an important contribution to predicting the perceptual consequences of eye movements. Focusing on cerebello-cortical pathways incorporating the central and ventral lateral thalamus, Prevosto and Sommer (2013) review evidence for thalamic modulation of movement processing based on cognitive requirements. Encompassing a number of thalamic nuclei, including the pulvinar, mediodorsal and ventral intermediate nuclei, Klostermann et al. (2013) discuss contributions of the thalamus and basal ganglia to language perception and production. The Research Topic continues on the theme of behavioral flexibility. Minamimoto et al. (2014) show that that the macaque centromedian nucleus, in the intralaminar thalamus, plays a role in counteracting behavioral biases, which contributes to flexible behavior via interactions with the basal ganglia. Bradfield et al. (2013) review evidence from rodent studies that another intralaminar thalamic nucleus, the parafascicular thalamus, also contributes to behavioral flexibility, whereas the mediodorsal thalamic nucleus plays a key role in acquiring goal-directed behavior. Next, the focus shifts to memory processes. Jankowski et al. (2013) review contributions of the anterior thalamus, and its interactions with the hippocampus and cortex, to memory processing and spatial navigation in rodents. This includes evidence for oscillatory activity at theta frequencies in the anterior thalamus. Habib et al. (2013) investigate memory processes in the auditory thalamus, showing differential molecular events underlying safety learning and fear conditioning. Finally, there are four reviews highlighting different functions of the large mediodorsal thalamic nucleus and its interactions with the prefrontal cortex in primates. Mitchell and Chakraborty (2013) discuss the effects of lesions of the mediodorsal thalamus, supporting its role in memory and other cognitive processes. Baxter (2013) argues that the mediodorsal thalamus regulates plasticity within prefrontal cortex as well as the flexibility of prefrontal-dependent operations. Funahashi (2013) reviews contributions of the mediodorsal thalamus to spatial working memory, including how interaction between the thalamus and prefrontal cortex can enable sensory-to-motor transformations of maintained information. To conclude, Saalmann (2014) proposes that the mediodorsal thalamus regulates synchrony between neurons in prefrontal cortex and, consequently, their information exchange according to cognitive control demands. This Research Topic highlights the key contributions of the thalamus to neural processing in cortico-cortical, hippocampo-cortical, cortico-striatal and cerebello-cortical pathways. Although the underlying mechanisms of thalamic influence on these pathways remain to be clarified, there is growing evidence that the thalamus plays a key role in dynamically routing information across the brain (Saalmann et al., 2012; Xu and Sudhof, 2013). Such a role may involve flexibly synchronizing ensembles of neurons, thereby configuring brain networks for the current behavioral context. Taken together, the articles in this Research Topic show that thalamic interactions with cortical and subcortical areas are integral to behavioral flexibility, memory processes and cognition in general.

Two experiments examined the effects of bilateral excitotoxic lesions of either the mediodorsal (MD) or anterior (ANT) thalamic nuclei on instrumental acquisition and performance, sensitivity to changes in the value of the instrumental outcome, and sensitivity to changes in the instrumental contingency. Rats were food deprived and trained to press two levers, each earning a unique food outcome (pellets or sucrose). All rats acquired the instrumental response although ANT lesions appear slightly to increase and MD lesions slightly to suppress instrumental performance. After training, specific satiety-induced devaluation of one of the two instrumental outcomes produced a selective reduction in responding on the lever that in training had earned the now devalued outcome but only in the SHAM and ANT groups. In contrast, MD animals failed to show evidence of a selective devaluation effect when tested in extinction. Additionally, SHAM and ANT animals selectively decreased responding when one action-outcome contingency was degraded, whereas MD animals reduced responding nonselectively on the two levers. Subsequent tests established that an inability to discriminate between either the two actions or the two outcomes cannot account for the lack of selective responding observed in the MD animals. Together these data suggest that MD lesions produce a profound deficit in the ability of rats to utilize specific action-outcome associations and appear to render rats relatively insensitive to the causal consequences of their instrumental actions. In contrast, far from producing a deficit, ANT lesioned rats were as sensitive to the effects of these behavioural manipulations as the sham lesioned controls.

Altered connections between the thalamus and the prefrontal cortex are often implicated in theories concerning the pathogenesis of schizophrenia. Using a model based on anatomically realistic connection patterns between thalamus and prefrontal cortex, we analyzed changes of prefrontal activity resulting from stimulation of the mediodorsal thalamus. Here we demonstrate that the specific influence of thalamo-cortical projections is smaller than the importance of intra-prefrontal connectivity in shaping prefrontal activity patterns. These results might be helpful in explaining experimentally observed hypo- and hyperactive states of prefrontal cortex in schizophrenic patients.

The likelihood of winning a bout of competitive behaviour is increased by past wins, and the neural circuitry underlying this crucial determinant of social rank in a group of mice is identified as a projection from the mediodorsal thalamus to the dorsomedial prefrontal cortex.

Progression into the basal temporal neocortex including portions of the fusiform and lingual gyri, involvement of superordinate olfactory centers and the limbic thalamus.

The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia., Highlights • There is heterogeneity in Group II receptor physiology across thalamic nuclei. • This differential distribution may facilitate multimodal thalamic nuclei functions. • Group II receptor activation reduced burst firing via reducing thalamic inhibition. • Increased thalamic inhibition precipitates impairments in cognitive function. • Activating the Group II receptors may therefore enhance cognitive function.

Schizophrenia is a serious and chronic brain disorder whose underlying neuropathology has proven difficult to identify. This article reviews the current status of neuropathological studies in terms of how they inform the diagnosis, pathogenesis, pathophysiology, and mechanisms of treatment of schizophrenia. Although additional studies are required, substantial data converge on the hypothesis that the pathophysiology of schizophrenia is associated with alterations in thalamic-prefrontal cortical connectivity.

We studied changes in thalamo-prefrontal cortical transmission in behaving mice following both low-frequency stimulation of the mediodorsal thalamus (MD) and during extinction of a conditioned fear response. Electrical stimulation of the MD induces a field potential in the medial prefrontal cortex (mPFC) characterized by two initial negative-positive complexes (N1-P1 and N2-P2) followed by two positive-negative complexes (P2-N3 and P3-N4). The N1-P1 and N2-P2 complexes were identified as resulting from orthodromic and antidromic prefrontal activation, respectively. Because the two complexes were not often easily dissociated, plasticity in the prefrontal synaptic transmission was considered to result from changes in N1-P2 amplitude. Low-frequency thalamic stimulation (1,200 pulses at 2 Hz) produced either long-term (at least 32 min) depression or potentiation of the N1-P2 amplitude. Mice submitted to fear conditioning (tone-shock association), displayed on the first day of extinction (tone-alone presentations) a strong freezing behavior, which decreased progressively, but was still high the following day. Extinction of conditioned fear was accompanied the first day by a depression of prefrontal transmission, which was converted into potentiation the following day. Potentiation of prefrontal transmission lasted at least 24 h following the second day of the fear extinction procedure. In conclusion, low-frequency thalamic stimulation can produce, in behaving mice, either depression or potentiation of prefrontal synaptic transmission. Decrease in prefrontal synaptic transmission observed during the first day of extinction may reflect processing of the high degree of predictiveness of danger (unconditioned stimulus: US) by the aversive conditioned stimulus (CS). However, the subsequent potentiation of transmission in the mPFC may be related to processing of cognitive information such as the CS will no longer be followed by the US, even if emotional response (freezing) to the CS is still high.

Interconnections among the ventral mesencephalon, nucleus accumbens, and ventral pallidum are critical in the initiation of adaptive behavioral responses to environmental stimuli. Within this circuit are two highly topographically organized subcircuits that are differentially interconnected with limbic and motor circuitry in the brain. However, there is not a great deal of anatomical interconnection between the limbic and motor subcircuits. A polysynaptic connection between the two subcircuits involves projections from the limbic ventral pallidum to the mediodorsal thalamus to the prefrontal cortex back to the motor regions of the nucleus accumbens. In the present report we show that this connection is critical in the expression of motor behavior elicited by opioids and the capacity of a rat to perform in a task requiring spatial working memory.

The mediodorsal thalamus (MD) is a crucial component of the neural network involved in the learning and generation of goal-directed actions. A series of experiments reported here examined the contributions of MD to the temporal differentiation of reward-guided actions. In Experiment 1, we trained rats on a discrete-trial, fixed-criterion temporal differentiation task, in which only lever presses exceeding a threshold duration value were rewarded. Pre-training MD lesions impaired temporal differentiation of action duration, by increasing the dispersion of the duration distribution. Post-training MD lesions also impaired differentiation, but by reducing the average emitted press durations, thus shifting the distribution without increasing the dispersion. In Experiment 2, we trained rats to space their lever pressing above criterion inter-press-intervals in order to earn rewards. Both pre-training and post-training MD lesions impaired the differentiation of inter-press-intervals. These results show that MD plays an important role in the acquisition and expression of action differentiation.

Thalamocortical loops, connecting functionally segregated, higher order cortical regions and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive-emotional integration, we applied high resolution fMRI on 7 Tesla.Using an event related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex (CM/PF). These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo-striato-cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behaviour such as sexual processing.

The glucose metabolism in the mediodorsal thalamus (MD) is increased in rats in the activity-based anorexia (ABA) model. In patients, electrical stimulation in hyperactive brain regions reduced symptoms in e.g. major depressive disorder and cluster headache. In two blinded randomised controlled experiments, we therefore examined the effects of high-frequency electrical stimulation and an electrolytic lesion in the MD in a validated rat model for anorexia nervosa. The ABA model was successfully replicated in all our experiments, with a reduction in body weight, food intake, and survival time and an increase in running activity. In a first experiment, we evaluated the effect of electrical stimulation or a curative lesion in the MD on survival, body weight, food intake and locomotor activity in ABA rats. Electrical MD stimulation or an electrolytic MD lesion did not improve the symptoms of rats in the ABA model, compared to control groups. In a second experiment, we investigated the effect of a preventive electrolytic lesion in the MD on rats in the ABA model. Although there was no significant improvement of survival, body weight and food intake, locomotor activity was significantly reduced in the lesion group compared to the control group. Apart from this positive effect on running activity, we found no convincing evidence for the suitability of the MD as a neuromodulation target for anorexia nervosa patients. ispartof: BRAIN RESEARCH BULLETIN vol:79 issue:2 pages:116-122 ispartof: location:United States status: published

In a previous experiment (Stokes & Best, 1988), we showed that rats lesioned in the mediodorsal nucleus of the thalamus performed poorly on a radial maze placed in a visually deprived environment. The present experiment was designed to assess performance of similarly lesioned rats on the radial maze when extramaze cues were plentiful. Sixteen rats were trained on the radial maze; 7 then received electrolytic lesion of the mediodorsal thalamic nucleus. Despite excellent preoperative acquisition of the task, postoperative performance was severely impaired in all animals given lesions. These animals made more errors, and made errors earlier in the session, than did control animals. Furthermore, animals with lesions developed stereotyped patterns of responding on the maze, as had animals in the previous study. Thus, we replicated our previous findings with respect to the effects of lesions of the mediodorsal nucleus, and extended their generality to a more usual, visually enriched testing environment. Our results indicate that the impairment in maze performance subsequent to mediodorsal thalamus lesion is nonspecific, affecting memory secondarily.

Neural activity was recorded from the mediodorsal thalamic nucleus of behaving rats during the discrimination of olfactory cues associated with or without a reward. Approximately 10% of mediodorsal thalamic neurons showed significant responses during the presentation of cues. Most of these neurons responded strongly to cues associated with a reward. These neurons also differentiated between cues, even in the same reinforcement (reward/nonreward) group. All of the neurons tested in extinction, relearning, and/or new-learning trials changed their responses flexibly according to the reward contingency. These neurons were located primarily in the central and medial segments of the mediodorsal thalamus. These results suggest that these mediodorsal thalamic neurons are the neural substrates for association learning of olfactory stimuli with rewards.

The aim of this study was to quantify the total number of neurons and glial cells in the mediodorsal nucleus of the thalamus (MD) of 8 newborn human brains, in comparison to 8 adult human brains. The estimates of the cell numbers were obtained using the stereological principles of the optical fractionator. In the case of the adults, the total number of neurons in the entire MD was an average of 41% lower than in the newborn, which was statistically highly significant (P < 0.001). The estimated average total number of neurons in MD thalamus of the newborns was 11.2 million (coefficient of variation [CV] = standard deviation/mean = 0.16), compared with the adults' 6.43 million (CV = 0.15). The glial cell numbers were substantially higher in the adult brains, with an increase of almost 4 times from 10.6 million at birth to 36.3 million in the fully developed adult brain. This is the first demonstration of a higher number of human neurons in the brain of newborns compared with the adult.

Publisher Summary This chapter focuses on the development of the rat prefrontal cortex (PFC). It also describes the size and development of connections with the thalamus, spinal cord and, other cortical areas. It also explores whether or not the prefrontal cortex has a later or prolonged development in comparison with other cortical areas. The pre- and postnatal development of the rat cerebral cortex is also reviewed in the chapter. The cortical areas that attain an adult-like myelinization pattern prior to birth all belong to sensoric/motoric areas. The development of the cortical layers, ingrowth of thalamic and dopaminergic fibers, follow a scheme of development that is comparable to that of other cortical areas. Only the volumetric development seems to point to a delayed maturation of the prefrontal areas, especially the orbital PFC. Reciprocal projection from the prefrontal cortex to the mediodorsal thalamus is largely formed during the second week of postnatal life. A way to monitor the development of the PFC is to measure its increase in size during the first postnatal months.