Analysis of projections from the medial prefrontal cortex to the thalamus in the rat, with emphasis on nucleus reuniens

The medial prefrontal cortex (mPFC) is involved in high‐order cognitive processes, including, but not limited to, decision making, goal directed behavior, and working memory. Although previous reports have included descriptions of mPFC projections to the thalamus in overall examinations of mPFC projections throughout the brain, no previous study has comprehensively examined mPFC projections to the thalamus. The present report compares and contrasts projections from the four divisions of the mPFC, i.e., the infralimbic, prelimbic, anterior cingulate and medial agranular cortices, to the thalamus in the rat by using the anterograde anatomic tracer Phaseolus vulgaris‐leucoagglutinin. We showed that (1) the infralimbic, prelimbic, anterior cingulate cortices distribute heavily and selectively to midline/medial structures of the thalamus, including the paratenial, paraventricular, interanteromedial, anteromedial, intermediodorsal, mediodorsal, reuniens, and the central medial nuclei; (2) the medial agranular cortex distributes strongly to the rostral intralaminar nuclei (central lateral, paracentral, central medial nuclei) as well as to the ventromedial and ventrolateral nuclei of thalamus; and (3) all four divisions of the mPFC project densely to the nucleus reuniens (RE) of the thalamus. The nucleus reuniens is the major source of thalamic afferents to the hippocampal formation. There are essentially no direct projections from the mPFC to the hippocampus. The present demonstration of pronounced mPFC projections to RE suggests that the nucleus reuniens is a critical relay in the transfer of information from the medial prefrontal cortex to the hippocampus. Our further demonstration of strong mPFC projections to several additional thalamic nuclei, particularly to the mediodorsal nucleus, suggests that these thalamic nuclei, like RE, represent important output stations (or gateways) for the actions of mPFC on diverse subcortical and cortical structures of the brain. J. Comp. Neurol. 442:163–187, 2002. © 2002 Wiley‐Liss, Inc.

[1]  Werner J. Schmidt,et al.  6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze , 1990, Behavioural Brain Research.

[2]  F. Wouterlood,et al.  Innervation of Entorhinal Principal Cells by Neurons of the Nucleus Reuniens Thalami. Anterograde PHA‐L Tracing Combined with Retrograde Fluorescent Tracing and Intracellular Injection with Lucifer Yellow in the Rat , 1991, The European journal of neuroscience.

[3]  L. Swanson,et al.  A direct projection from Ammon's horn to prefrontal cortex in the rat , 1981, Brain Research.

[4]  Bryan Kolb,et al.  Functions of the frontal cortex of the rat: A comparative review , 1984, Brain Research Reviews.

[5]  M. Petrides Dissociable Roles of Mid-Dorsolateral Prefrontal and Anterior Inferotemporal Cortex in Visual Working Memory , 2000, The Journal of Neuroscience.

[6]  J. Price,et al.  The organization of the thalamocortical connections of the mediodorsal thalamic nucleus in the rat, related to the ventral forebrain–prefrontal cortex topography , 1992, The Journal of comparative neurology.

[7]  B. Kirkpatrick,et al.  Forebrain connections of medial agranular cortex in the prairie vole, Microtus ochrogaster , 1999, Experimental Brain Research.

[8]  H. Groenewegen,et al.  Nuclear origin of thalamic afferents of the ventral striatum determines their relation to patch/matrix configurations in enkephalin-immunoreactivity in the rat. , 1988, Journal of chemical neuroanatomy.

[9]  R. Moore,et al.  Efferent projections of the paraventricular thalamic nucleus in the rat , 1995, The Journal of comparative neurology.

[10]  M Petrides,et al.  Impairments on nonspatial self-ordered and externally ordered working memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the monkey , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  P. Goldman-Rakic,et al.  Delay-related activity of prefrontal neurons in rhesus monkeys performing delayed response , 1982, Brain Research.

[12]  R. Robertson,et al.  Thalamic connections with limbic cortex. I. Thalamocortical projections , 1981, The Journal of comparative neurology.

[13]  T. Jay,et al.  Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal–prefrontal cortex long-term potentiation , 1999, Neuroscience.

[14]  H. Groenewegen,et al.  Patterns of convergence and segregation in the medial nucleus accumbens of the rat: Relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents , 1995, The Journal of comparative neurology.

[15]  P. Goldman-Rakic,et al.  Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. , 1989, Journal of neurophysiology.

[16]  G. N. Brito,et al.  Septohippocampal system and the prelimbic sector of frontal cortex: A neuropsychological battery analysis in the rat , 1990, Behavioural Brain Research.

[17]  B H Bland,et al.  Discharge patterns of hippocampal theta-related cells in the caudal diencephalon of the urethan-anesthetized rat. , 1995, Journal of neurophysiology.

[18]  B Poucet,et al.  Working memory, response selection, and effortful processing in rats with medial prefrontal lesions. , 1994, Behavioral neuroscience.

[19]  R. Llinás,et al.  The neuronal basis for consciousness. , 1998, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[20]  R. Vertes PHA‐L analysis of projections from the supramammillary nucleus in the rat , 1992, The Journal of comparative neurology.

[21]  M P Witter,et al.  Projections from the nucleus reuniens thalami to the entorhinal cortex, hippocampal field CA1, and the subiculum in the rat arise from different populations of neurons , 1996, The Journal of comparative neurology.

[22]  H. Groenewegen,et al.  Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat , 1991, Neuroscience.

[23]  K. Sukekawa Reciprocal connections between medial prefrontal cortex and lateral posterior nucleus in rats. , 1988, Brain, behavior and evolution.

[24]  M. Witter,et al.  Projection from the nucleus reuniens thalami to the hippocampal region: Light and electron microscopic tracing study in the rat with the anterograde tracer Phaseolus vulgaris‐leucoagglutinin , 1990, The Journal of comparative neurology.

[25]  S. Sesack,et al.  Hippocampal afferents to the rat prefrontal cortex: Synaptic targets and relation to dopamine terminals , 1996, The Journal of comparative neurology.

[26]  Bruno Poucet,et al.  Working memory, response selection, and effortful processing in rats with medial prefrontal lesions , 1994 .

[27]  H. Groenewegen,et al.  Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum , 1990, The Journal of comparative neurology.

[28]  Larry W. Swanson,et al.  Brain Maps: Structure of the Rat Brain , 1992 .

[29]  K. Otake,et al.  Single midline thalamic neurons projecting to both the ventral striatum and the prefrontal cortex in the rat , 1998, Neuroscience.

[30]  T. Jay,et al.  Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris‐leucoagglutinin , 1991, The Journal of comparative neurology.

[31]  R. Mair,et al.  The effects of frontal cortical lesions on remembering depend on the procedural demands of tasks performed in the radial arm maze , 1997, Behavioural Brain Research.

[32]  Serge Laroche,et al.  Long-term potentiation in the prefrontal cortex following stimulation of the hippocampal CA1/subicular region , 1990, Neuroscience Letters.

[33]  P. Goldman-Rakic,et al.  The Issue of Memory in the Study of Prefrontal Function , 1994 .

[34]  M. Mishkin,et al.  Non-spatial memory after selective prefrontal lesions in monkeys , 1978, Brain Research.

[35]  A. Rosenquist,et al.  Afferent connections of the thalamic intralaminar nuclei in the cat , 1985, Brain Research.

[36]  R. Mair,et al.  A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat , 1996, Behavioural Brain Research.

[37]  O. Phillipson,et al.  Afferent projections to the dorsal thalamus of the rat as shown by retrograde lectin transport—I. The mediodorsal nucleus , 1988, Neuroscience.

[38]  P. Goldman-Rakic,et al.  Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey , 1984, Neuroscience.

[39]  Brian H. Bland,et al.  The medial septum: Node of the ascending brainstem hippocampal synchronizing pathways. , 2000 .

[40]  G. Paxinos The Rat nervous system , 1985 .

[41]  M. Yanagihara,et al.  Thalamic projections to the hippocampal and entorhinal areas in the cat , 1987, The Journal of comparative neurology.

[42]  J. Price,et al.  The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat , 1977, The Journal of comparative neurology.

[43]  Martin Deschênes,et al.  The organization of corticothalamic projections: reciprocity versus parity , 1998, Brain Research Reviews.

[44]  R. Reep,et al.  Topographic organization of the striatal and thalamic connections of rat medial agranular cortex , 1999, Brain Research.

[45]  A. B. Mulder,et al.  Short‐ and Long‐term Plasticity of the Hippocampus to Nucleus Accumbens and Prefrontal Cortex Pathways in the Rat, In Vivo , 1997, The European journal of neuroscience.

[46]  R. Romo,et al.  Neuronal correlates of parametric working memory in the prefrontal cortex , 1999, Nature.

[47]  A. Stevens,et al.  A comparison of temporal decay in place memory tasks in rats (Rattus norvegicus) with lesions affecting thalamus, frontal cortex, or the hippocampal system. , 1996, Behavioral neuroscience.

[48]  Atsutaka Hashimoto,et al.  Afferent connections of medial precentral cortex in the rat , 1984, Neuroscience Letters.

[49]  R P Kesner,et al.  Differential involvement of the dorsal anterior cingulate and prelimbic-infralimbic areas of the rodent prefrontal cortex in spatial working memory. , 1998, Behavioral neuroscience.

[50]  N. McNaughton,et al.  Supramammillary cell firing and hippocampal rhythmical slow activity. , 1991, Neuroreport.

[51]  E. Irle,et al.  Widespread cortical projections of the hippocampal formation in the cat , 1982, Neuroscience.

[52]  B. Kolb Animal models for human PFC-related disorders. , 1990, Progress in brain research.

[53]  C. Leonard,et al.  The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections. , 1969, Brain research.

[54]  T. Jay,et al.  NMDA Receptor‐dependent Long‐term Potentiation in the Hippocampal Afferent Fibre System to the Prefrontal Cortex in the Rat , 1995, The European journal of neuroscience.

[55]  J. Glowinski,et al.  Anatomical and electrophysiological evidence for a direct projection from ammon's horn to the medial prefrontal cortex in the rat , 2004, Experimental Brain Research.

[56]  Françoise Condé,et al.  Afferent connections of the medial frontal cortex of the rat. A study using retrograde transport of fluorescent dyes. I. Thalamic afferents , 1990, Brain Research Bulletin.

[57]  Bryan Kolb,et al.  Chapter 25 Animal models for human PFC-related disorders , 1991 .

[58]  R. Vertes,et al.  Phase relations of rhythmic neuronal firing in the supramammillary nucleus and mammillary body to the hippocampal theta activity in urethane anesthetized rats , 1997, Hippocampus.

[59]  Sheng Chen,et al.  Afferent connections of the thalamic paraventricular and parataenial nuclei in the rat — a retrograde tracing study with iontophoretic application of Fluoro-Gold , 1990, Brain Research.

[60]  T. Jay,et al.  Plasticity of the hippocampal-prefrontal cortex synapses , 1996, Journal of Physiology-Paris.

[61]  R. M. Beckstead An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal‐projection (prefrontal) cortex in the rat , 1979, The Journal of comparative neurology.

[62]  H. Spinnler The prefrontal cortex, Anatomy, physiology, and neuropsychology of the frontal lobe, J.M. Fuster. Raven Press, New York (1980), IX-222 pages , 1981 .

[63]  J. Seamans,et al.  D1 Receptor Modulation of Hippocampal–Prefrontal Cortical Circuits Integrating Spatial Memory with Executive Functions in the Rat , 1998, The Journal of Neuroscience.

[64]  H. Groenewegen Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography , 1988, Neuroscience.

[65]  I. Divac,et al.  Selective ablations within the prefrontal cortex of the rat and performance of delayed alternation , 1978 .

[66]  G Mann,et al.  ON THE THALAMUS * , 1905, British medical journal.

[67]  Javier Quintana,et al.  Prefrontal representation of stimulus attributes during delay tasks. I. Unit activity in cross-temporal integration of sensory and sensory-motor information , 1988, Brain Research.

[68]  R. J. McDonald,et al.  Dissociation of the medial prefrontal, posterior parietal, and posterior temporal cortex for spatial navigation and recognition memory in the rat. , 1994, Cerebral cortex.

[69]  M. Seki,et al.  Anterior thalamic afferents from the mamillary body and the limbic cortex in the rat , 1984, The Journal of comparative neurology.

[70]  H. Groenewegen,et al.  Connections of the parahippocampal cortex in the cat. II. Subcortical afferents , 1986, The Journal of comparative neurology.

[71]  R. Vertes,et al.  Characterization of neurons of the supramammillary nucleus and mammillary body that discharge rhythmically with the hippocampal theta rhythm in the rat , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[72]  J. Price,et al.  The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. , 2000, Cerebral cortex.

[73]  H. Shibata,et al.  Efferent projections from the anterior thalamic nuclei to the cingulate cortex in the rat , 1993, The Journal of comparative neurology.

[74]  H. Groenewegen,et al.  The specificity of the ‘nonspecific’ midline and intralaminar thalamic nuclei , 1994, Trends in Neurosciences.

[75]  C. Cavada,et al.  Allocortical afferent connections of the prefrontal cortex of the cat , 1983, Brain Research.

[76]  H. Yamada,et al.  Efferent connections of the nucleus reuniens and the rhomboid nucleus in the rat: an anterograde PHA-L tracing study , 1989, Neuroscience Research.

[77]  T. Jay,et al.  Selectivity of the hippocampal projection to the prelimbic area of the prefrontal cortex in the rat , 1989, Brain Research.

[78]  M. Petrides,et al.  Specialized systems for the processing of mnemonic information within the primate frontal cortex. , 1996, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[79]  T. Jay,et al.  Rapid increase in PKA activity during long‐term potentiation in the hippocampal afferent fibre system to the prefrontal cortex in vivo , 1998, The European journal of neuroscience.

[80]  Tanemichi Chiba,et al.  Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat: an anterograde tracer PHA-L study , 1991, Brain Research.

[81]  S. Petersen,et al.  Frontal cortex contributes to human memory formation , 1999, Nature Neuroscience.

[82]  J. Seamans,et al.  Functional differences between the prelimbic and anterior cingulate regions of the rat prefrontal cortex. , 1995, Behavioral neuroscience.

[83]  P. Goldman-Rakic Cellular basis of working memory , 1995, Neuron.

[84]  F. Reinoso-suárez,et al.  Topographical organization of the afferent connections of the principal ventromedial thalamic nucleus in the cat , 1985, The Journal of comparative neurology.

[85]  E. Audinat,et al.  Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents , 1995, The Journal of comparative neurology.

[86]  D. Powell,et al.  Efferent connections of the medial prefrontal cortex in the rabbit , 1994, Experimental Brain Research.

[87]  J. Seamans,et al.  Selective Roles for Hippocampal, Prefrontal Cortical, and Ventral Striatal Circuits in Radial-Arm Maze Tasks With or Without a Delay , 1997, The Journal of Neuroscience.

[88]  C. Saper,et al.  Efferent projections of the infralimbic cortex of the rat , 1991, The Journal of comparative neurology.

[89]  H. Groenewegen,et al.  The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. , 1990, Progress in brain research.

[90]  W. Cowan,et al.  A study of subcortical afferents to the hippocampal formation in the rat , 1979, Neuroscience.

[91]  G. F. Tremblay,et al.  The Prefrontal Cortex , 1989, Neurology.

[92]  R. M. Beckstead,et al.  Convergent thalamic and mesencephalic projections to the anterior medial cortex in the rat , 1976, The Journal of comparative neurology.

[93]  R. Desimone,et al.  Neural Mechanisms of Visual Working Memory in Prefrontal Cortex of the Macaque , 1996, The Journal of Neuroscience.

[94]  R. Roth,et al.  Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: An anterograde tract‐tracing study with Phaseolus vulgaris leucoagglutinin , 1989, The Journal of comparative neurology.

[95]  H. E. Rosvold,et al.  Localization of function within the dorsolateral prefrontal cortex of the rhesus monkey. , 1970, Experimental neurology.

[96]  K. Uchizono Characteristics of Excitatory and Inhibitory Synapses in the Central Nervous System of the Cat , 1965, Nature.

[97]  L. Swanson,et al.  The structural organization of connections between hypothalamus and cerebral cortex 1 Published on the World Wide Web on 2 June 1997. 1 , 1997, Brain Research Reviews.

[98]  J M Wyss,et al.  Projections from the laterodorsal nucleus of the thalamus to the limbic and visual cortices in the rat , 1992, The Journal of comparative neurology.

[99]  Richard Passingham,et al.  Delayed matching after selective prefrontal lesions in monkeys (Macaca mulatta) , 1975, Brain Research.

[100]  K. Nakano,et al.  Cortical and brain stem afferents to the ventral thalamic nuclei of the cat demonstrated by retrograde axonal transport of horseradish peroxidase , 1985, The Journal of comparative neurology.

[101]  M. Hasselmo Septal Modulation of Hippocampal Dynamics: What Is the Function of the Theta Rhythm? , 2000 .

[102]  M. Bentivoglio,et al.  Thalamic midline cell populations projecting to the nucleus accumbens, amygdala, and hippocampus in the rat , 1990, The Journal of comparative neurology.

[103]  J. Michael Wyss,et al.  Efferent connections of the anteromedial nucleus of the thalamus of the rat , 1999, Brain Research Reviews.

[104]  M. Herkenham The afferent and efferent connections of the ventromedial thalamic nucleus in the rat , 1979, The Journal of comparative neurology.

[105]  S. Finger,et al.  Behavioral effects of large and small lesions of the rat medial frontal cortex , 2004, Experimental Brain Research.

[106]  M. Herkenham The connections of the nucleus reuniens thalami: Evidence for a direct thalamo‐hippocampal pathway in the rat , 1978, The Journal of comparative neurology.

[107]  P. Gisquet-Verrier,et al.  Prelimbic cortex specific lesions disrupt delayed-variable response tasks in the rat. , 1996, Behavioral neuroscience.

[108]  J. Aggleton,et al.  The effects of fornix and medial prefrontal lesions on delayed non-matching-to-sample by rats , 1993, Behavioural Brain Research.

[109]  T. van Groen,et al.  Extrinsic projections from area CA1 of the rat hippocampus: Olfactory, cortical, subcortical, and bilateral hippocampal formation projections , 1990, The Journal of comparative neurology.

[110]  R. Moore,et al.  Diencephalic and brainstem afferents to the hippocampal formation of the rat , 1981, Brain Research Bulletin.

[111]  H Niki,et al.  Prefrontal unit activity during delayed alternation in the monkey. I. Relation to direction of response. , 1974, Brain research.

[112]  C. V. van Eden,et al.  Acquisition of conditional associations and operant delayed spatial response alternation: effects of lesions in the medial prefrontal cortex. , 1988, Behavioral neuroscience.

[113]  P. Goldman-Rakic,et al.  Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task. , 1998, Journal of neurophysiology.

[114]  P. Gisquet-Verrier,et al.  Lesions of the prelimbic-infralimbic cortices in rats do not disrupt response selection processes but induce delay-dependent deficits: evidence for a role in working memory? , 1999, Behavioral neuroscience.

[115]  R. T. Watson,et al.  Efferent Connections of the Rostral Portion of Medial Agranular Cortex in Rats , 1987, Brain Research Bulletin.

[116]  H. Groenewegen,et al.  Efferent connections of the prelimbic (area 32) and the infralimbic (area 25) cortices: An anterograde tracing study in the cat , 1985, The Journal of comparative neurology.

[117]  R. Kesner,et al.  Prefrontal cortex and working memory for spatial response, spatial location, and visual object information in the rat. , 1996, Cerebral cortex.

[118]  M. F. Huerta,et al.  Differential thalamic connectivity of rostral and caudal parts of cortical area Fr2 in rats , 1991, Brain Research.

[119]  H. Uylings,et al.  The role of the medial prefrontal cortex of rats in short-term memory functioning: further support for involvement of cholinergic, rather than dopaminergic mechanisms , 1995, Brain Research.

[120]  P. Goldman-Rakic,et al.  Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic "scotomas" , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[121]  R. Vertes,et al.  Neuronal Networks That Control the Septal Pacemaker System: Synaptic Interconnections Between the Septal Complex, Hippocampus, Supramammillary Area, and Median Raphe , 2000 .

[122]  R. Vertes,et al.  Afferent projections to nucleus reuniens of the thalamus , 2004, The Journal of comparative neurology.

[123]  P. Gisquet-Verrier,et al.  Functional role of rat prelimbic-infralimbic cortices in spatial memory: evidence for their involvement in attention and behavioural flexibility , 2000, Behavioural Brain Research.

[124]  T. Sawaguchi,et al.  Properties of delay-period neuronal activity in the monkey dorsolateral prefrontal cortex during a spatial delayed matching-to-sample task. , 1999, Journal of neurophysiology.

[125]  R. Vertes,et al.  Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. , 1997, Neuroscience.