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Neurosciences, Ottawa Health Research Institute, Ottawa Hospital Civic Site, and University of Ottawa, Ottawa, Ontario, K1Y 4E9, Canada
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We used patch-clamp
recordings in slice preparations from Sprague-Dawley rats to evaluate
responses of 20 spinal-projecting neurons in the dorsal paraventricular
nucleus (PVN) to electrical stimulation in suprachiasmatic nucleus
(SCN). Neurons containing a retrograde label transported from the
thoracic (T1-T4) intermediolateral column
displayed three intrinsic properties that collectively allowed
distinction from neighboring parvocellular or magnocellular cells: a
low-input resistance, a hyperpolarization-activated time-dependent inward rectification, and a low-threshold calcium conductance. Twelve
of fifteen cells tested responded to electrical stimulation in SCN. All
of 10 cells tested in media containing
2,3,-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (5 µM) and
D(
)-2-amino-5-phosphonopentanoic acid (20 µM)
responded with constant latency (11.4 ± 0.7 ms) inhibitory postsynaptic potentials, able to follow 20- to 50-Hz stimulation and
blockable with bicuculline (20 µM). By contrast, all eight cells
tested in the presence of bicuculline demonstrated constant latency
(9.8 ± 0.6 ms) excitatory postsynaptic potentials that followed
at 20-50 Hz and featured both
non-N-methyl-D-aspartate (NMDA) and NMDA
receptor-mediated components. We conclude that both GABAergic and
glutamatergic neurons in SCN project directly to spinal-projecting
neurons in the dorsal PVN.
retrograde labeling; rhodamine microspheres; intrinsic conductances; hyperpolarization-activated inward rectification; T current
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ADAPTATION TO DAILY CHANGES in the environment is reflected in circadian rhythmicity in a wide array of physiological and behavioral activities that occur over a period of ~24 h. In mammals, these fluctuations can be traced to the hypothalamic suprachiasmatic nucleus (SCN), a structure whose neurons contain "clock" genes that regulate an intrinsic oscillatory mechanism but whose activities can also be entrained to the light-dark cycle by inputs via retinohypothalamic and geniculohypothalamic afferents. Lesion and transplantation studies have clearly documented that circadian rhythmicity in any number of physiological functions depends on the integrity of the SCN and that SCN efferent pathways are largely responsible for subsequent entrainment of brain functions (17, 25). SCN projects heavily to areas of the hypothalamus (2, 17, 41), a brain region that contains the paraventricular nucleus (PVN), recognized as a critical center for homeostasis (34). PVN encompasses distinct populations of magnocellular and parvocellular neurons whose outputs include projections to the posterior pituitary for control of body fluid balance, the median eminence for adenohypophysial regulation, and brain stem and spinal cord for influencing autonomic output functions (35). The latter includes a population of parvocellular neurons located in the dorsal cap region of PVN, whose axons project to brain stem and spinal "autonomic" centers (4, 14, 19, 23, 27, 33, 34). Recent anatomic tracer studies reveal that the dorsal cap area of PVN receives an innervation from the SCN (2, 37, 39), a connection that may identify a neuronal circuitry that participates in the entrainment of a circadian rhythmicity in autonomic variables such as blood pressure (20), heart rate (26), and body temperature (10, 31). However, little is known at the cellular level about the functional features of such an innervation. To address this issue, we first used rhodamine latex microspheres to retrogradely label dorsal PVN neurons projecting axons to the thoracic spinal cord. We then used patch-clamp recording techniques to record from these identified neurons in hypothalamic rat brain slice preparations and characterize both their intrinsic properties and responses to focal electrical stimulation in SCN. We now report that these neurons have distinct electrical properties and that activation of SCN efferents monosynaptically evokes postsynaptic responses in a majority of tested dorsal PVN neurons, mediated via GABAergic and glutamatergic receptors.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Retrograde labeling. Sprague-Dawley rats (12-14 days) of either sex were initially anesthetized with methoxyflurane (Janssen). The spinal cord at the T1-T4 level was exposed by dorsal laminectomy, and 1 µl of a rhodamine-labeled fluorescent microspheres suspension (FluoSpheres, 0.04 µm, red fluorescence 580/605; Molecular Probes, Eugene, OR) was slowly injected into the region of the intermediolateral cell column. Animals were returned to their cages for 2-3 days, sufficient to permit retrograde transport to the hypothalamus.
Slice preparation.
On the day of experiment, animals were killed by decapitation and the
brain was rapidly removed and placed in ice-cold oxygenated (95%
O2-5% CO2) artificial cerebrospinal fluid
(ACSF) composed of (in mM) 124 NaCl, 3.2 KCl, 26.2 NaHCO3,
1.3 MgCl2, 1 NaH2PO4, 10 glucose,
and 2.4 CaCl2 at pH of 7.4. A coronal section 250- to
300-µm thick containing the PVN and the SCN in the same plane (see
Fig. 1D) was cut with a tissue
slicer (Leica VT1000S, Leica), trimmed, preincubated in ACSF for 1 h, and then transferred to a submerged chamber for recording at room
temperature.
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Electrophysiology.
Retrogradely labeled neurons were visualized with an upright microscope
equipped with a fluorescent attachment and a port for a differential
interference contrast camera (Hamamatsu C2400, Japan) and monitor unit.
Recordings were obtained during the subjective dark period (of a
12:12-h light-dark cycle) using glass micropipettes (borosilicate
glass; OD 1.5 mm; ID 1.1 mm) filled with a solution containing (in mM)
135 K gluconate, 10 KCl, 10 HEPES, 1 EGTA, 2 Mg-ATP, and 0.2 GTP at pH
7.3 and osmolarity of 285 mosM. We obtained patch-clamp data from both
labeled and unlabeled neurons. Lucifer yellow (1 mg/ml) was included in
the pipette to verify the morphology of recorded cells. Recording
pipettes had an open resistance of 3-7 M
and seal resistances
>3 G. The series resistance was estimated in brief voltage clamp
sessions from the whole cell capacitive current in response to a
voltage pulse; with whole cell recording, the estimated series
resistance was generally <20 M. A concentric bipolar electrode
(outside diameter of 325 µm, tip-ring separation of 100 µm; FHC)
positioned in the SCN was connected to a stimulus isolation unit that
delivered electrical pulses (duration 0.5 ms; intensity 5-15 V)
under software control. Data obtained with an Axopatch 1-D amplifier
(Axon Instruments) were low-pass filtered at 2 kHz. pClamp 8.0 software
(Axon Instruments) was used for data acquisition and analysis. Values
of membrane potential were corrected for liquid junction potential.
Results are expressed as means ± SE.
Histological identification. Slices were fixed in 4% paraformdehyde in 0.1 M PBS overnight, reimmersed in PBS containing 20% sucrose (wt/vol), and double-labeled neurons were visualized with a BIORAD 1024 confocal microscope (excitation/emission settings of 568/585 and 488/515 for rhodamine and Lucifer yellow, respectively). Images of 20-40 1-µm sections were projected onto a single panel (Fig. 1, A-C).
Pharmacology.
The following drugs from Tocris Cookson (Ballwin, MO) were bath applied
at concentrations indicated in the text: ()-bicuculline methochloride; D()-2-amino-5-phosphonopentanoic acid
(D-AP5); 2,3,-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Lucifer yellow was from Sigma (St. Louis, MO).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Properties of spinal-projecting PVN neurons.
Data were obtained from 20 retrogradely labeled cells in the dorsal
PVN. These cells displayed oblong, bipolar, or tripolar neuronal somata
measuring 15-20 µm in the long axis, with two to three main
dendrites that were oriented along the mediolateral axis. Some cells
had dendrites that branched extensively, occasionally extending into
the magnocellular or medial periventricular part of the nucleus. An
axon could often be visualized arising from a main dendrite. Cells
displayed a resting membrane potential of 59.7 ± 0.9 mV and
time constant of 53.2 ± 5.1 ms. Action potentials had an
amplitude, width (at half of amplitude), and threshold of 69.5 ± 2.3 mV, 2.3 ± 0.2 ms, and 34.0 ± 0.6 mV, respectively, and were followed by a prominent afterhyperpolarization (AHP) of
18.5 ± 1.5 mV (measured between threshold and peak of negativity).
was significantly lower (P < 0.05) than that obtained among a population of
magnocellular neurons (864 ± 51.4 M; n = 40 cells; see Ref. 6) or parvocellular neurons located in the
periventricular or ventrolateral PVN (772 ± 48 M;
n = 49 cells). Second, a majority (16/20) of these
neurons displayed a slow time-dependent hyperpolarization-activated
inward rectification (Fig. 2,
Aa and c), blockable with bath applications of cesium (Fig. 2Ab) or ZD-7288 (Fig.
2B), identifying this current as an IH
conductance. IH is a feature of many central neurons, including those in the hypothalamic supraoptic nucleus (11, 12). Third, these cells displayed a prominent low-threshold spike (LTS) when depolarized from a hyperpolarized holding potential (Fig. 3A) or on return from a
hyperpolarized potential (Fig. 3B). The activation curve
(Fig. 3B, inset) and sensitivity of this LTS to
nickel (Fig. 3C) are features consistent with the existence of a low-threshold calcium conductance, a property previously noted in
an unidentified population of parvocellular PVN neurons (15,
36).
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Response to SCN stimulation.
In 15 of 20 retrogradely labeled neurons, orientation of the slice
permitted observations on their response to SCN stimulation. Of these,
12 neurons displayed an evoked response and 3 did not respond to SCN
stimulation. When recorded in ACSF, this featured an inhibitory
postsynaptic potential (IPSP) as the dominant response in four neurons,
whereas a mixed inhibitory and excitatory response was seen in eight
cells. To minimize possible competing conductances, IPSPs in 10 cells
were characterized in the presence of glutamate receptor antagonists
D-AP5 (20 µM) and NBQX (5 µM). At suprathreshold stimulation strengths, latencies of evoked IPSPs ranged from 9.2 to
15.2 ms (mean 11.4 ± 0.7 ms). In individual cells, latencies remained constant over a range of stimulation intensities and followed
stimulation frequencies of 20-50 Hz (Fig.
4), features compatible with a
monosynaptic response (1). Mean IPSP rise rate and decay
times were 0.85 ± 0.33 mV/ms and 87 ± 15 ms, respectively, when measured at membrane potentials held at 75 to 80 mV.
SCN-evoked IPSPs reversed at 65 mV, close to the chloride equilibrium
potential under current conditions and were reversibly blocked with 20 µM bicuculline, indicating mediation via GABAA receptors
(Fig. 4A).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Spinal-projecting PVN neurons exhibit unique membrane properties. Retrograde tracers have been useful in demonstrating that parvocellular neurons in the dorsal and ventrolateral PVN project to autonomic sites in brain stem and spinal cord (14, 27, 28, 33). In the present study, we employed latex microspheres to identify these neurons for patch-clamp analyses. Previous reports have indicated that this marker remains localized to the site of injection, transports readily to the somata, and remains intact for prolonged periods without degeneration or diffusion to extracellular structures and, importantly, is apparently devoid of toxicity to neurons (9, 38). An added benefit is the relative ease with which doubly labeled neurons can be revealed with laser scan confocal microscopy without further resectioning.
Although this is not the first report where electrophysiology has been applied to spinal-projecting PVN neurons (13, 18), the data presented here illustrate some intrinsic electrical properties that are distinct from either neighboring magnocellular or parvocellular cells. In particular, magnocellular PVN neurons, previously classified as type I (36), demonstrate a frequency-dependent action potential broadening and a transient outward conductance but lack a low-threshold calcium conductance; these properties can influence their spike patterning and the magnitude of secretion of neurohypophysial hormones (24). Heterogeneity among parvocellular PVN neurons has also been recognized in earlier investigations leading to the designation of type II (nonburst LTS) and type III (burst LTS) neurons; both types show a time-independent inward rectification, with the latter showing a large LTS that triggers a burst of action potentials (15, 36). In an earlier study (15), we also referred to type IV parvocellular neurons; these cells featured a low-input resistance, not unlike the neurons described and identified here as spinal-projecting neurons. Evidently, spinal-projecting neurons in the dorsal PVN also have IH and low-threshold calcium conductances. Further studies can now proceed on the significance of such conductances in modulating activity patterns and input-output relationships and their functional implications for neurotransmission to target neurons.SCN projects monosynaptically to spinal-projecting PVN neurons. Although there is ample evidence that SCN entrains a diurnal rhythmicity in various physiological functions that are under control of spinal autonomic output, the mechanisms as to how SCN neurons convey information to PVN and other central nervous system (CNS) areas are still in need of clarification. Although there is some indication that humoral mechanisms may contribute (29), the existence of a prominent efferent axonal projection system suggests that the entrainment by SCN of CNS neurons is likely to depend heavily on the integrity of these neuronal pathways that connect SCN to its target cells. Earlier anatomic tracer studies were consistent in revealing not only a dense SCN innervation to the dorsomedial hypothalamic nucleus and the sub-PVN zone but also in demonstrating that PVN is one of the targets for SCN efferents (2, 30, 41). Of particular note are recent double-label studies that reveal fibers from SCN coursing into the medial and dorsal PVN, in close apposition to spinal-projecting neurons (37, 39). An analysis at the ultrastructural level to verify that these SCN efferents project directly to dorsal PVN neurons has not yet been reported. However, observations reported here implying a monosynaptic pattern in SCN-evoked postsynaptic responses are consistent with a direct innervation of spinal-projecting PVN neurons.
Some concerns arise owing to the apparent duality in these evoked responses, in large measure because of immunocytochemical observations that most, but not all, SCN neurons contain glutamic acid decarboxylase and/or GABA (3, 8, 21, 22). This would imply that the output of SCN is largely GABAergic and therefore inhibitory in nature (21). Indeed, the electrophysiology supports this notion for the SCN innervation to magnocellular PVN neurons (6, 16). Although there is strong support for the GABAergic nature of most SCN efferents, it remains to be explained how an "inhibitory" output system might exert opposing (facilitatory vs. suppressant) influences on target neurons. One theory, yet to be confirmed, advanced by Wagner et al. (40) is that SCN neurons might undergo a diurnal shift in their chloride reversal potential, thereby permitting activated GABAA receptors to depolarize postsynaptic neurons. An alternative possibility arising from our current and earlier electrophysiological studies (16) is the existence of a glutamatergic projection from SCN, most easily demonstrable in slice preparations after pharmacological blockade of GABAA receptors. The unpredictability of glutamate-like immunoreactivity combined with the undisputed evidence for GABA in most SCN neurons argues against this postulate. Indeed, with electrical stimulation there is always the concern that the glutamate-mediated excitation we have reported in PVN does not come from SCN but rather is due to current spread to axons in passage or adjacent (non-SCN) neurons. Although this may be possible, we have noted that electrical stimulation in the hypothalamus lateral to a knife cut placed at the edge of the SCN was ineffective, contrasting with monosynaptic EPSCs and IPSCs evocable from an intra-SCN stimulation site. We also reported earlier that intra-SCN chemical (glutamate) microstimulation (to depolarize somata but not axons) in the presence of bicuculline can increase the frequency of EPSPs and evokes membrane depolarization in parvocellular PVN neurons (16), implying that a component of the SCN output is glutamatergic. A more reliable indication can be found in a recently reported study revealing the presence in SCN of a (relatively small) subpopulation of glutamatergic/aspartatergic neurons, identified through their ability to transport [D-3H]aspartate retrogradely from PVN (5). Perhaps the projections from this subpopulation of SCN neurons can explain the electrophysiological observations of SCN-evoked glutamatergic responses in neurons in PVN (6, 16), supraoptic nucleus (7), and ventromedial preoptic area (32).Perspectives
The presence of diurnal rhythms in various physiological functions affects our ability to cope with environmental challenges such as shift work and jet lag, situations that may impair sleep-wake cycles and cognitive functions. While this topic has obvious practical and clinical interest, our understanding of the detailed cellular mechanisms whereby the biological clock in our brain entrains systems of neurons regulating homeostasis and various autonomic activities is far from complete. The present study adds to a growing body of evidence that supports a direct influence, via axonal projections, of SCN on the excitability of neurons engaged in homeostasis and the regulation of autonomic functions. Our data support the presence of both GABA and glutamate as mediators of rapid inhibitory and excitatory neurotransmission, respectively, from SCN to these target neurons. This concurs not only with earlier demonstrations of a prominent GABAergic cell composition within SCN (8, 21), but also recent evidence that a subpopulation of PVN-projecting SCN neurons is glutamatergic (5). Among the next challenges will be an understanding of the relative contributions of these subpopulations of SCN neurons in the entrainment of target cells at various stages of the circadian cycle.| |
ACKNOWLEDGEMENTS |
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The authors thank A. Ridsdale for technical assistance with confocal imaging.
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FOOTNOTES |
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We gratefully acknowledge the support of the Canadian Heart and Stroke Foundation (HSF) and the Canadian Institutes for Health Research (CIHR). L.-N. Cui was the recipient of an HSF Fellowship and L. P. Renaud held a CIHR Senior Scientist award.
Address for reprint requests and other correspondence: L. P. Renaud, Neurology/Neurosciences, Ottawa Hospital, 1053 Carling Ave., Ottawa, Ontario, Canada K1Y 4E9 (E-mail: lprenaud{at}ohri.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 February 2001; accepted in final form 20 June 2001.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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  D.-P. Li, Q. Yang, H.-M. Pan, and H.-L. Pan Plasticity of pre- and postsynaptic GABAB receptor function in the paraventricular nucleus in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H807 - H815. [Abstract] [Full Text] [PDF]
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 M. D. Womack, R. Morris, T. C. Gent, and R. Barrett-Jolley Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus Circ. Res., June 8, 2007; 100(11): 1650 - 1658. [Abstract] [Full Text] [PDF]
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 D.-P. Li and H.-L. Pan Glutamatergic Inputs in the Hypothalamic Paraventricular Nucleus Maintain Sympathetic Vasomotor Tone in Hypertension Hypertension, April 1, 2007; 49(4): 916 - 925. [Abstract] [Full Text] [PDF]
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Y.-F. Li, K. L. Jackson, J. E. Stern, B. Rabeler, and K. P. Patel Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2847 - H2856. [Abstract] [Full Text] [PDF]
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 K. Jackson, H. M. V. Silva, W. Zhang, L. C. Michelini, and J. E. Stern Exercise Training Differentially Affects Intrinsic Excitability of Autonomic and Neuroendocrine Neurons in the Hypothalamic Paraventricular Nucleus J Neurophysiol, November 1, 2005; 94(5): 3211 - 3220. [Abstract] [Full Text] [PDF]
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 K. J. Latchford and A. V. Ferguson Angiotensin depolarizes parvocellular neurons in paraventricular nucleus through modulation of putative nonselective cationic and potassium conductances Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2005; 289(1): R52 - R58. [Abstract] [Full Text] [PDF]
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D.-P. Li, L. M. Atnip, S.-R. Chen, and H.-L. Pan Regulation of Synaptic Inputs to Paraventricular-Spinal Output Neurons by {alpha}2 Adrenergic Receptors J Neurophysiol, January 1, 2005; 93(1): 393 - 402. [Abstract] [Full Text] [PDF]
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D.-P. Li, S.-R. Chen, and H.-L. Pan VR1 Receptor Activation Induces Glutamate Release and Postsynaptic Firing in the Paraventricular Nucleus J Neurophysiol, September 1, 2004; 92(3): 1807 - 1816. [Abstract] [Full Text] [PDF]
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H. M. Stauss Heart rate variability Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R927 - R931. [Full Text] [PDF]
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Q. H. Chen, J. R. Haywood, and G. M. Toney Sympathoexcitation by PVN-Injected Bicuculline Requires Activation of Excitatory Amino Acid Receptors Hypertension, October 1, 2003; 42(4): 725 - 731. [Abstract] [Full Text] [PDF]
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 D.-P. Li, S.-R. Chen, and H.-L. Pan Angiotensin II Stimulates Spinally Projecting Paraventricular Neurons through Presynaptic Disinhibition J. Neurosci., June 15, 2003; 23(12): 5041 - 5049. [Abstract] [Full Text] [PDF]
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 V. Simonneaux and C. Ribelayga Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters Pharmacol. Rev., June 1, 2003; 55(2): 325 - 395. [Abstract] [Full Text] [PDF]
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D.-P. Li, S.-R. Chen, and H.-L. Pan Nitric Oxide Inhibits Spinally Projecting Paraventricular Neurons Through Potentiation of Presynaptic GABA Release J Neurophysiol, November 1, 2002; 88(5): 2664 - 2674. [Abstract] [Full Text] [PDF]
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S. Michel, J. Itri, and C. S. Colwell Excitatory Mechanisms in the Suprachiasmatic Nucleus: The Role of AMPA/KA Glutamate Receptors J Neurophysiol, August 1, 2002; 88(2): 817 - 828. [Abstract] [Full Text] [PDF]
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) and under steady state (
) illustrate
inward rectification under control conditions. Plots with round symbols
(
, 
) reveal the loss of this
rectification in the presence of cesium. B: sample voltage
traces from another dorsal PVN spinal-projecting neuron illustrate
response to hyperpolarizing current pulses. Recordings were obtained in
nominally calcium-free ACSF to eliminate the low-threshold spike (LTS).
Note the IH sag in the control trace (arrow) is absent
after addition of 60 µM ZD-7288.
