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.

1.
Van Eden CG: Development of connections between the mediodorsal nucleus of the thalamus and the prefrontal cortex in the rat. J Comp Neurol 1986;244:349-359.
2.
Molnar Z: Development and evolution of thalamocortical interactions. Eur J Morphol 2000;38:313-320.
3.
Byne W, Buchsbaum MS, Kemether E, Purohit P, Haroutunian V, Jones L: Postmortem assessment of thalamic nuclear volumes in schizophrenia. Am J Psychiatry 2001;159:59-65.
4.
Faull RL, Mehler WR: Thalamus; in Paxinos G (ed): The Rat Nervous System. Forebrain and Midbrain. New York, Academic Press, 1985, vol 1, pp 129-161.
5.
Negyessy L, Goldman-Rakic PS: Morphometric characterization of synapses in the primate prefrontal cortex formed by afferents from the mediodorsal thalamic nucleus. Exp Brain Res 2005;64:148-154.
6.
Benes FM: Myelination of cortical-hippocampal relays during late adolescence. Schizophr Bull 1989;15:585-593.
7.
Rajan I, Cline HT: Glutamate receptor activity is required for normal development of tectal cell dendrites in vivo. J Neurosci 1998;18:7836-7846.
8.
Van Ooyen A, van Pelt J, Corner MA: Implication of activity-dependent neurite outgrowth for neuronal morphology and network development. J Theor Biol 1995;172:63-82.
9.
Chakravarthy B, Morley P, Whitfield J: Ca2+-calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. Trends Neurosci 1999;22:12-16.
10.
Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, Soderling TR: Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 2006;50:897-909.
11.
Gerendasy D: Homeostatic tuning of Ca2+ signal transduction by members of the calpacitin protein family. J Neurochem Res 1999;58:107-119.
12.
Zou D-J, Cline HT: Postsynaptic calcium/calmodulin-dependent protein kinase II is required to limit elaboration of presynaptic and postsynaptic neuronal arbors. J Neurosci 1999;19:8909-8918.
13.
Borodinsky LN, Coso OA, Fiszman ML: Contribution of Ca2+ calmodulin-dependent kinase II and mitogen-activated protein kinase to neural activity-induced neurite outgrowth and survival of cerebellar granule cells. J. Neurochem 2002;80:1062-1070.
14.
Mainen ZF, Sejnowski TJ: Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 1996;382:363-366.
15.
Hely TA, Graham B, van Ooyen A: A computational model of dendritic elongation and branching based on MAP2 phosphorylation. J Theor Biol 2001;210:375-384.
16.
Diez-Guerra FJ, Avila J: An increase in phosphorylation of microtubule-associated protein 2 accompanies dendrite extension during the differentiation of cultured hippocampal neurons. Eur J Biochem 1994;227:68-77.
17.
Audesirk G, Cabell L, Kern M: Modulation of neurite branching by protein phosphorylation in cultured rat hippocampal neurons. Dev Brain Res 1997;102:247-260.
18.
Stoeckli ET: What does the developing brain tell us about neural disease? Eur J Neurosci 2012;35:1811-1817.
19.
Harrison LM, Mair RG: A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat. Behav Brain Res 1996;75:195-206.
20.
Stokes KA, Best PJ: Mediodorsal thalamic lesions impair ‘reference' and ‘working' memory in rats. Physiol Behav 1990;47:471-476.
21.
Isseroff A, Rosvold HE, Galkin TW, Goldman-Rakic PS: Spatial memory impairments following damage to the mediodorsal nucleus of the thalamus in rhesus monkeys. Brain Res 1982;232:97-113.
22.
Aggleton JP, Mishkin M: Visual recognition impairment following medial thalamic lesions in monkeys. Neuropsychologia 1983;21:189-197.
23.
Garter JA, de Bruin JP: Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat. Brain Res 1992;580:12-17.
24.
Sircar R, Rudy JW: Repeated neonatal phencyclidine treatment impairs performance of a spatial table in juvenile rats. Ann NY Acad Sci 1998;844:303-309.
25.
Sircar R: Postnatal phencyclidine-induced deficit in adult water maze performance is associated with N-methyl-D-aspartate receptor upregulation. Int J Dev Neurosci 2003;21:159-167.
26.
Stefani MR, Moghaddam B: Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 2005;57:433-436.
27.
Wang C, McInnis J, Ross-Sanchez M, Shin-nick-Gallagheere P, Wiley JL, Johnson KM: Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 2001;107:535-550.
28.
Pehrson AL, Walenting DM, Wood JT, Vunck SA, Porter JH: Early postnatal antagonism of glutamatergic NMDA receptors impairs reference and working memory performances, but has no effect on locomotor activity in male C57Bl/6 mice. 2007;18:S1-S11.
29.
Bubenikova-Valesova V, Horacek J, Vrajova M, Hoschl C: Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Behav Rev 2008;32:1014-1023.
30.
Gabbott PL, Warner TA, Jays PR, Bacon SJ: Areal and synaptic interconnectivity of prelimbic (area 32), infralimbic (area 25) and insular cortices in the rat. Brain Res 2003;993:59-71.
31.
Paxinos G, Kus L, Ashwell KW, Watson C: Chemoarchitectonic Atlas of the Rat Forebrain. London, Academic Press, 1999.
32.
Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. Sydney, Academic Press, 1986.
33.
Pirot S, Jay TM, Glowinski J, Thierry AM: Anatomical and electrophysiological evidence for an excitatory amino acid pathway from the thalamic mediodorsal nucleus to the prefrontal cortex. J Neurosci 1994;6:1225-1234.
34.
Negyessy L, Hámori J, Bentivoglio M: Contralateral cortical projection to the mediodorsal thalamic nucleus: origin and synaptic organization in the rat. Neuroscience 1998;84:741-753.
35.
Kuroda M, Murakami K, Kishi K, Price JL: Thalamic synapses between axons from the mediodorsal thalamic nucleus and pyramidal cells in the prelimbic cortex of the rat. J Comp Neurol 1995;356:143-151.
36.
Kuroda M, Murakami K, Shinkai M, Ojima H, Kishi K: Electron microscopic evidence that axon terminals from the mediodorsal thalamic nucleus make direct synaptic contacts with callosal cells in the prelimbic cortex of the rat. Brain Res 1995;677:348-353.
37.
Kuroda M, Yokofujita J, Murakami K: An ultrastructural study of the neural circuit between the prefrontal cortex and the mediodorsal nucleus of the thalamus. Prog Neurobiol 1998;54:417-458.
38.
Jones L, Johnson N, Byne W: Alterations in MAP2 staining in area 9 and 32 of schizophrenic prefrontal cortex. Psychiatry Res 2002;114:137-148.
39.
Pakkenberg B: Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 1990;47:1023-1028.
40.
Pakkenberg B: The volume of the medial dorsal thalamic nucleus in treated and untreated schizophrenics. Schizophr Res 1992;7:95-100.
41.
Popken GJ, Bunney WE Jr, Potkin SG, Jones EG: Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci USA 2000;97:9276-9280.
42.
Young KA, Manaye KF, Liang C-L, Hicks PB, German DC: Reduced numbers of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 2000;47:944-953.
43.
Byne W, Buchsbaum MS, Kemether E, Hazlett EA, Shinwari A, Mitropoulou V, Siever LJ: Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 2001;58:133-140.
44.
Staal WG, Hulshoff Pol HE, Schnack HG, Hoogendoorn ML, Jellema K, Kahn RS: Structural brain abnormalities in patients with schizophrenia and their healthy siblings. Am J Psychiatry 2000;157:416-421.
45.
Berendse HW, Groenewegen HJ: Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 1991;42:73-102.
46.
Kolb B, Cioe J: Recovery from early cortical damage in rats. VIII. Earlier may be worse: behavioral dysfunction and abnormal cerebral morphogenesis following perinatal frontal cortical lesions in the rat. Neuropharmacology 2000;39:756-764.
47.
Volk DW, Lewis DA: Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry: implications for schizophrenia. Biol Psychiatry 2003;53:385-389.
48.
Gizerian SS, Marrow AL, Lieberman JA, Grobin AC: Neonatal neurosteroid administration alters parvalbumin expression and neuron number in medial dorsal thalamus of adult rats. Brain Res 2004;1012:66-74.
49.
Ma L, Harada T, Harada C, Romero M, Herbet JM, McConnell SK, Parada LF: Neurotrophin-3 is required for appropriate establishment of thalamocortical connections. Neuron 2002;36:623-634.
50.
Berry M: Development of the cerebral neocortex of the rat; in Gottlieb G (ed): Aspects of Neurogenesis. New York, Academic Press, 1974, vol 2, pp 7-67.
51.
Sinopoli KJ, Floresco SB, Galea LA: Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory. Neurobiol Learn Mem 2006;86:293-304.
52.
Gisquet-Verrier P, Delatour B: The role of the rat prelimbic/infralimbic cortex in working memory: not involved in the short-term maintenance but in the monitoring and processing functions. Neuroscience 2006;141:585-596.
53.
Flores G, Alquicer G, Silva-Gomez AB, Zaldivar G, Stewart J, Quirion R, Srivastava LK: Alterations in dendritic morphology of prefrontal cortical and nucleus accumbens neurons in post-pubertal rats after neonatal excitotoxic lesions of the ventral hippocampus. Neuroscience 2005;133:463-470.
54.
Van Pelt J, van Ooyen A, Corner MA: Growth cone dynamics and activity-dependent processes in neuronal network development. Prog Brain Res 1996;108:333-346.
55.
Kossel AH, Williams CV, Schweizer M, Ka-ter SB: Afferent innervation influences the development of dendritic branch and spines via both activity-dependent and non-activity-dependent mechanisms. J Neurosci 1997;17:6314-6324.
56.
Baker RE, van Pelt J: Cocultured, but not isolated, cortical explants display normal dendritic development: a long-term quantitative study. Dev Brain Res 1997;98:21-29.
57.
Wise SP, Fleshman JW, Jones EG: Maturation of pyramidal cell form in relation to developing afferent and efferent connections of the rat somatic sensory cortex. J Neurosci 1979;4:1275-1297.
58.
Callaway JC, Lasser-Ross N, Ross WN: IPSPs strongly inhibit climbing fiber-activated [Ca2+]i increases in the dendrites of cerebellar Purkinje neurons. J Neurosci 1995;15:2777-2787.
59.
Magee JC, Johnston D: Synaptic activation of voltage-gated channels in the dendrites of hippocampal pyramidal neurons. Science 1995;268:301-304.
60.
Magee JC, Johnston D: Characterization of single voltage-gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J Physiol 1995;487:67-90.
61.
de la Pena E, Geijo-Barrientos E: Laminar localization, morphology, and physiology properties of pyramidal neurons that have the low-threshold calcium current in guinea pig medial frontal cortex. J Neurosci 1996;16:5301-5311.
62.
Gillessen T, Alzheimer C: Amplification of EPSPs by low Ni2+ and amiloride-sensitive Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J Neurosci 1997;77:1639-1643.
63.
Ramakers GJ, Avci B, van Hulten P, van Ooyen A, van Pelt J, Pool CW, Lequin MB: The role of calcium signaling in early axonal and dendritic morphogenesis of rat cerebral cortex neurons under non-stimulated growth conditions. Dev Brain Res 2001;126:163-172.
64.
Petit TL, LeBoutillier JC, Gregorio A, Libstug H: The pattern of dendritic development in the cerebral cortex of the rat. Dev Brain Res 1988;41:209-219.
65.
Kater SB, Mattson MP, Cohan C, Connor J: Calcium regulation of the neuronal growth cone. Trends Neurosci 1988;11:315-321.
66.
Broadbelt K, Byne WB, Jones LB: Evidence for a decrease in primary and secondary basilar dendrites on pyramidal cells in area 32 of schizophrenic prefrontal cortex. Schizophr Res 2002;58:75-81.
67.
Broadbelt K, Ramprasaud A, Jones LB: Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. Schizophr Res 2006;87:6-14.
68.
Broadbelt K, Jones LB: Evidence of altered calmodulin immunoreactivity in areas 9 and 32 of prefrontal schizophrenic prefrontal cortex. J Psychiatr Res 2008;42:612-621.
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