Early postnatal lesion of the medial dorsal nucleus leads to loss of dendrites and spines in adult prefrontal cortex.

Research suggests that the medial dorsal nucleus (MD) of the thalamus influences pyramidal cell development in the prefrontal cortex (PFC) in an activity-dependent manner. The MD is reciprocally connected to the PFC. Many psychiatric disorders, such as schizophrenia, affect the PFC, and one of the most consistent findings in schizophrenia is a decrease in volume and neuronal number in the MD. Therefore, understanding the role the MD plays in the development of the PFC is important and may help in understanding the progression of psychiatric disorders that have their root in development. Focusing on the interplay between the MD and the PFC, this study examined the hypothesis that the MD plays a role in the dendritic development of pyramidal cells in the PFC. Unilateral electrolytic lesions of the MD in Long-Evans rat pups were made on postnatal day 4 (P4), and the animals developed to P60. We then examined dendritic morphology by examining MAP2 immunostaining and by using Golgi techniques to determine basilar dendrite number and spine density. Additionally, we examined pyramidal cell density in cingulate area 1 (Cg1), prelimbic region, and dorsolateral anterior cortex, which receive afferents from the MD. Thalamic lesions caused a mean MD volume decrease of 12.4% which led to a significant decrease in MAP2 staining in both superficial and deep layers in all 3 cortical areas. The lesions also caused a significant decrease in spine density and in the number of primary and secondary basilar dendrites on superficial and deep layer pyramidal neurons in all 3 regions. No significant difference was observed in pyramidal cell density in any of the regions or layers, but a nonsignificant increase in cell density was observed in 2 regions. Our data are thus consistent with the hypothesis that the MD plays a role in the development of the PFC and, therefore, may be a good model to begin to examine neurodevelopmental disorders such as autism and schizophrenia.

Functional interaction of medial mediodorsal thalamic nucleus but not nucleus accumbens with amygdala and orbital prefrontal cortex is essential for adaptive response selection after reinforcer devaluation.

In nonhuman primates, reward-based decision making may be assessed through choices of objects overlying two different foods, one of which has been devalued by selective satiation. The most adaptive object choices yield the food of higher value. A large body of data identifies the amygdala and orbital prefrontal cortex (PFo) as neural mediators of adaptive responses to reinforcer devaluation. More recent work in nonhuman primates reveals the critical role of the medial, magnocellular portion of the mediodorsal nucleus of the thalamus (MDm) as well. Because both the nucleus accumbens (NA) and the MDm are anatomically related to the amygdala and PFo, and because both regions are implicated in reward processing, we tested whether either region necessarily interacts with the amygdala and PFo to mediate reinforcer devaluation effects. We used a crossed-disconnection design in which monkeys received amygdala and PFo lesions in one hemisphere combined with either NA or MDm lesions in the contralateral hemisphere. Monkeys that sustained NA disconnection, like controls, showed robust shifts in object choices in response to reinforcer devaluation. In contrast, monkeys that sustained MDm disconnection failed to adjust their object choices. Thus, MDm, but not NA, works together with the amygdala and PFo to support reward-based decision making.

The magnocellular mediodorsal thalamus is necessary for memory acquisition, but not retrieval.

Damage to the magnocellular mediodorsal thalamic nucleus (MDmc) in the human brain is associated with both retrograde and anterograde amnesia. In the present study we made selective neurotoxic MDmc lesions in rhesus monkeys and compared the effects of these lesions on memory acquisition and retrieval. Monkeys learned 300 unique scene discriminations preoperatively and retention was assessed in a one-trial preoperative retrieval test. Bilateral neurotoxic lesions of the MDmc, produced by 10 x 1 microl injections of a mixture of ibotenate and NMDA did not affect performance in the postoperative one-trial retrieval test. In contrast, new postoperative learning of a further 100 novel scene discriminations was substantially impaired. Thus, MDmc is required for new learning of scene discriminations but not for their retention and retrieval. This finding is the first evidence that MDmc plays a specific role in memory acquisition.

Deficits in prospective memory following damage to the medial subdivision of the mediodorsal thalamic nucleus.

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.

Dissociable performance on scene learning and strategy implementation after lesions to magnocellular mediodorsal thalamic nucleus.

Monkeys with aspiration lesions of the magnocellular division of the mediodorsal thalamus (MDmc) are impaired in object-in-place scene learning, object recognition, and stimulus-reward association. These data have been interpreted to mean that projections from MDmc to prefrontal cortex are required to sustain normal prefrontal function in a variety of task settings. In the present study, we investigated the extent to which bilateral neurotoxic lesions of the MDmc impair a preoperatively learnt strategy implementation task that is impaired by a crossed lesion technique that disconnects the frontal cortex in one hemisphere from the contralateral inferotemporal cortex. Postoperative memory impairments were also examined using the object-in-place scene memory task. Monkeys learnt both strategy implementation and scene memory tasks separately to a stable level preoperatively. Bilateral neurotoxic lesions of the MDmc, produced by 10 x 1 microl injections of a mixture of ibotenate and NMDA did not affect performance in the strategy implementation task. However, new learning of object-in-place scene memory was substantially impaired. These results provide new evidence about the role of the magnocellular mediodorsal thalamic nucleus in memory processing, indicating that interconnections with the prefrontal cortex are essential during new learning, but are not required when implementing a preoperatively acquired strategy task. Thus, not all functions of the prefrontal cortex require MDmc input. Instead, the involvement of MDmc in prefrontal function may be limited to situations in which new learning must occur.

A limited role for mediodorsal thalamus in devaluation tasks.

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 vs. 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.

Effects of ibotenic acid lesions of the mediodorsal thalamus on memory: relationship with emotional processes in mice.

The effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on memory and fear reactivity in mice were studied. In the first experiment, MD subjects were submitted to a behavioral design allowing to study the relationship between memory and anxiety [Krazem A, Borde N, Beracochea D. Effects of diazepam and beta-CCM on working memory in mice: relationship with emotional reactivity. Pharmacol Biochem Behav 2001;68:235-44; Beracochea D, Krazem A, Jaffard R. Methyl beta carboline-3-carboxylate reverses the working memory deficits induced either by chronic alcohol consumption or mammillary body lesions in mice. Psychobiology 1995;23:52-8]. In a second experiment, MD-lesioned subjects were submitted to a GO/NOGO temporal alternation task involving two intertrial intervals (ITIs: 0 and 30 s). Lesioned subjects exhibited large bilateral mediodorsal thalamic lesions with small damage into the centromedial thalamic nucleus. In the first experiment, MD-lesioned animals performed normally a sequential alternation task involving fixed ITIs over seven successive trials (5 or 30 s); in contrast, MD-lesioned subjects exhibited deficits in the sequential task involving the same but mixed ITIs (30-5 s versus 5-30 s) the deficit being observed for the last trials of the series, regardless the ITIs used. MD lesions increased fear reactivity in an elevated-plus maze, and scores of anxiety were negatively correlated with performance in the mixed alternation schedule. The second experiment involving non spatial information extended results of the first experiment in showing that the deficit of MD-lesioned animals was not dependent on the ITIs separating trials. Overall, our data show that MD-lesioned subjects exhibit a cognitive impairment characterized by a difficulty to maintain an alternation rule in situations involving procedural variance, and this deficit could stem primarily from an increase of fear reactivity.

Lesion of central part of the dorsomedial nucleus alters vasopressin but not corticotropin releasing hormone mRNA levels in rat hypothalamic paraventricular nucleus.

Functional significance of neural projections from the hypothalamic dorsomedial nucleus (DMN) to the paraventricular nucleus (PVN) was investigated using surgical lesion of the central part of the DMN. Under basal conditions, DMN lesion resulted in a decrease in magnocellular vasopressin (AVP) mRNA levels in the PVN, rise in pituitary proopiomelancortin (POMC) mRNA concentrations and elevated plasma corticosterone levels. Corticotropin-releasing hormone (CRH) mRNA levels remained unaffected. In sham operated animals, osmotic stress induced by hypertonic saline injection failed to modify AVP mRNA, but increased CRH and POMC mRNA levels and peripheral hormone release. The rise in CRH mRNA levels after osmotic stress was potentiated in DMN lesioned animals. Thus, the DMN participates in the control of hypothalamic peptide gene expression and pituitary adrenocorticotropic function.