viernes, 26 de febrero de 2010

Reconocimiento social y vasopresina

Nature advance online publication 24 February 2010 | doi:10.1038/nature08826; Received 9 April 2009; Accepted 12 January 2010; Published online 24 February 2010

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition

Vicky A. Tobin1,7, Hirofumi Hashimoto1,7, Douglas W. Wacker1, Yuki Takayanagi2, Kristina Langnaese3, Celine Caquineau1, Julia Noack3,4, Rainer Landgraf5, Tatsushi Onaka2, Gareth Leng1, Simone L. Meddle1,6, Mario Engelmann3 & Mike Ludwig1
  1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK
  2. Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
  3. Institute of Biochemistry and Cell Biology,
  4. Centre for Cellular Imaging and Innovative Disease Models, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
  5. Max Planck Institute of Psychiatry, 80804 Munich, Germany
  6. The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9PS, UK
  7. These authors contributed equally to this work.
Correspondence to: Mike Ludwig1 Correspondence and requests for materials should be addressed to M.L. (Email: mike.ludwig@ed.ac.uk).
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Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader–Willi syndrome, affective disorders and obsessive–compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism2, 3. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.
Complex social behaviour often depends on individual recognition, and most mammals distinguish individuals by their olfactory signatures. Some individuals are accorded a particular status, such as when a bond is formed between a mother and offspring, or between sexual partners in monogamous species. In these cases, an olfactory memory is forged in the olfactory bulb, partly as a result of the actions of peptides4. For example, oxytocin released in the mother’s brain during parturition helps to establish the olfactory signatures of the offspring as memorable5.
The converse of social attachment is rejection of, or aggression towards, individuals who are recognized as intruders or competitors6. For this, vasopressin, a peptide closely related to oxytocin, is important through its actions at V1 receptors, and mice without functional accessory olfactory systems show many of the same behavioural deficits as mice that lack V1 receptors. This suggests that vasopressin is involved in the processing and/or integration of olfactory stimuli, and that it couples socially relevant olfactory cues to an appropriate behavioural response7.
We have identified a hitherto unreported population of vasopressin neurons in the olfactory bulb (Fig. 1). We first saw these cells in a transgenic rat line in which enhanced green fluorescent protein (eGFP) was targeted to the vasopressin secretory pathway, resulting in its co-packaging with vasopressin in secretory vesicles8. The main olfactory bulb contains similar numbers of eGFP-expressing cells in males and females (99 ± 14 and 103 ± 10 cells per section, respectively; n = 16 in each case), giving an estimated 5,000–7,000 neurons per bulb; the accessory bulbs contained ~1,000 neurons. These large ovoid neurons (~15 μm in diameter) are mostly located in the external plexiform layer close to the glomeruli (the structures in the bulb that directly receive inputs from olfactory receptor cells). Each has several large dendrites, one of which penetrates a single glomerulus, where it gives rise to many small branches. This suggests that the neurons receive direct inputs from olfactory nerve afferents. Other dendrites travel laterally to the external zones around neighbouring glomeruli (Fig. 1a, b). Using immunocytochemistry, we showed that these cells indeed synthesize vasopressin (Fig. 1c, d), and we confirmed their presence in wild-type rats (Fig. 1e). We also confirmed that they express vasopressin messenger RNA, using in situ hybridization (Fig. 1f), and that vasopressin is released from olfactory bulb explants in vitro in response to depolarization using K+ in high concentration (release increased from 0.65 ± 0.19 to 4.88 ± 1.88 pg per sample; P < 0.01, n = 9). The total bulb vasopressin content was 42.9 ± 2.6 pg mg-1 wet weight (n = 12; mixed sex).
Figure 1: Vasopressin neurons in the olfactory bulb.
Figure 1 : Vasopressin neurons in the olfactory bulb. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma, Most vasopressin cells in eGFP transgenic rats (3,3′-diaminobenzidine staining) are in the periglomerular region throughout the main olfactory bulb. b, An apical dendrite ramifies into a glomerulus (blue staining, periglumerular cell-marker calbindin-D28k). c–e, Confirmation using antibodies against GFP (c) and vasopressin (d) in transgenic rats and vasopressin in wild-type rats (e). f, In situ hybridization for vasopressin mRNA. g–l, Vasopressin cells do not co-express calbindin, calretinin or GABA (red; g–i), but do contain glutamate (j–l). m–o, Fluorogold-labelling after injection into the anterior olfactory nucleus in mitral and periglomerular cells, but not vasopressin cells. p–r, V1a receptors are expressed on mitral cells and many periglomerular neurons (p), but not on vasopressin cells (q), whereas some vasopressin cells express V1b receptors (r). s, Patch-clamp recordings indicate firing patterns (spontaneous and depolarized) like those of external tufted cells10. GCL, granule cell layer; MCL, mitral cell layer; EPL, external plexiform layer; GL, glomerular layer. Scale bars, 20 μm.
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Unlike periglomerular cells and short axon cells (two other cell populations in the same region), the vasopressin cells are immunonegative for GABA (γ-aminobutyric acid), calretinin and calbindin-D28k (Fig. 1g–i), but like external tufted cells9, 10, they are immunoreactive for glutamate (Fig. 1j–l). No cells were immunoreactive for oxytocin. Whole-cell patch-clamp recordings from olfactory bulb slices showed that the vasopressin cells have electrophysiological characteristics like those of external tufted cells10. They show spontaneous bursts of action potentials (1.5 bursts per second) arising at the start of a slow depolarizing potential envelope (6.5 ± 0.5 mV; n = 5) that grows from a resting membrane potential of -55 ± 2 mV, and have an input resistance of 189 ± 38 MΩ. This bursting is voltage dependent (Fig. 1s), and injection of depolarizing current converts bursts of action potentials to an irregular firing pattern.
Unlike most external tufted cells, most vasopressin cells do not project outside the olfactory bulb. Microinjections of the retrograde tracer Fluorogold into the cortical amygdala, the piriform cortex or the olfactory tubercle (major projection sites of olfactory bulb efferents11) resulted in labelling of most mitral cells (the main output neurons) but no vasopressin cells (Fig. 1m–o), whereas injections into the anterior olfactory nucleus produced a very small number of labelled cells (data not shown). If the vasopressin cells do not project outside the olfactory bulb, any effects of the vasopressin that they release on olfactory information flow must be reflected by changes in the activity of other output cells. Vasopressin may be released from their axon terminals, but the dendrites may be a more important source as they are densely filled with vasopressin, and in the hypothalamus vasopressin is released from dendrites in both an activity-dependent manner and in an activity-independent way by agents that mobilize intracellular calcium12.
Vasopressin receptors are widespread in the main and accessory olfactory bulbs13. We found no immunoreactivity for V1a receptors on vasopressin cells, but some for V1b receptors (Fig. 1p–r), so vasopressin may act as an autocrine regulator through this receptor subtype14. Many other cells in the periglomerular region were immunoreactive for both subtypes, as were mitral cells in the main and accessory bulbs.
We tested the hypothesis that olfactory bulb vasopressin is involved in social recognition. It has already been shown that infusion of vasopressin into the bulb can enhance social recognition in rats. In those experiments, a peptide V1 receptor antagonist had no significant effect15. Here we used a non-peptide V1 receptor antagonist (OPC-21268) that diffuses more readily, and which is effective in antagonizing the actions of dendritically released vasopressin in the hypothalamus16. We injected the antagonist bilaterally into the olfactory bulb and tested social discrimination17. In this test, a juvenile rat is placed in the home cage of an adult male and the time that the adult spends investigating it is measured. Later, the same juvenile and an unfamiliar juvenile are introduced into the cage. Normally the adult investigates the familiar juvenile only briefly, and pays most attention to the unfamiliar juvenile; this memory is short lasting (<40 min) and is based on olfactory characteristics. In these experiments, we gave the adults a microinjection of the antagonist just before the juvenile was first presented. When retested, the adults did not discriminate between the familiar and unfamiliar juveniles, indicating that no memory of the juvenile was retained (analysis of variance: F(3, 39) = 3.34, P = 0.026; Fig. 2a, b).
Figure 2: Effects of V1a receptor blockade and vasopressin cell destruction on social recognition.
Figure 2 : Effects of V1a receptor blockade and vasopressin cell destruction on social recognition. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma, A juvenile (J) is presented to an adult male (A) for 4 min. This juvenile is removed and after 30 or 180 min is re-presented together with a non-familiar juvenile, and the preference index (Methods Summary) is calculated. b, Administration of V1 receptor antagonist results in performance similar to that after extinction of short-term discrimination (after 180 min). c, V1a receptor siRNA similarly impairs discrimination after 4, 8 and 16 d of treatment. d, Selective destruction of vasopressin cells by means of diphtheria toxin injection results in a similar impairment of discrimination in transgenic rats, but not in wild-type rats. Data shown, mean + s.e.m; *P < 0.05 and **P < 0.001 versus control; for each group, n is shown at the bottom of the corresponding column.
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To test involvement of the V1a receptor subtype specifically, we used infusions of a small interference RNA (siRNA) targeted against V1a receptor mRNA (siRNA has previously been used to silence gene expression successfully, including silencing the V2 receptor in mouse kidney18); these infusions produced transfection in the olfactory bulb but not in the septum (Supplementary Fig. 1). The effects of siRNA treatment were similar to those obtained with antagonist (treatment: F(1, 16) = 17.86, P < 0.01; factor interaction: F(3, 48) = 4.37, P < 0.01; Fig. 2c). Control rats (but not siRNA-treated rats) could recognize juveniles by their complex individual olfactory fingerprint even in the presence of distracting monomolecular odours (Supplementary Fig. 2a). Treatment with siRNA impaired habituation/dishabituation to juvenile cues (control: F(4, 32) = 3.42, P < 0.02; siRNA: F(4, 32) = 0.47, P = 0.76), but not to volatile odours (control: F(4, 32) = 5.672, P < 0.01; siRNA: F(4, 32) = 4.09, P < 0.01) or object recognition (Fig. 3a–c), and did not affect open-field behaviour (Supplementary Fig. 2b, c).
Figure 3: Specificity of effects on social recognition.
Figure 3 : Specificity of effects on social recognition. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma, Control rats and siRNA-treated rats show similar habituation and dishabituation to volatile scents. b, Control rats also show habituation and dishabituation to juveniles, whereas siRNA-treated rats show neither. c, Neither siRNA nor diphtheria toxin injection affects object recognition. Data shown, mean + s.e.m.; *P < 0.05 versus trial 4 and same treatment; n shown for each group in c.
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We also used a transgenic rat line in which the human diphtheria toxin receptor is inserted into the vasopressin promoter region. In these rats, infusion of diphtheria toxin19, 20 results in a local, selective destruction of vasopressin cells. Transgenic rats pretreated with toxin infusions into the olfactory bulb showed a similar impairment of juvenile recognition (treatment: F(1, 29) = 14.95, P < 0.01; factor interaction: F(1, 29) = 4.99, P = 0.033; Fig. 2d), again with no impairment of object recognition (Fig. 3c), locomotor activity or anxiety-related behaviours (Supplementary Fig. 2d–i).
Finally, we investigated vasopressin-dependent changes in olfactory bulb output. Current theories of glomerular function propose that olfactory nerve afferents activate external tufted cells, which activate short axon cells and periglomerular interneurons of the same glomerulus. This amplifies the olfactory nerve input and imposes on it a bursting pattern10, and this signal is transmitted to mitral cells. We recorded signals from mitral cells antidromically identified by electrical stimulation of the lateral olfactory tract in freely breathing, anaesthetized rats (Fig. 4a, b and Supplementary Fig. 3).
Figure 4: Vasopressin effects on mitral cells.
Figure 4 : Vasopressin effects on mitral cells. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma, b, Effects of vasopressin (a) and V1 receptor antagonist (b) on firing rate (a) and instantaneous frequency in a single, representative mitral cell (a, b). The inset in a shows raw waveform traces of spike activity. c, The activity quotient decreases in six cells treated with 4 ng vasopressin and seven cells treated with 40 ng vasopressin, and increases in seven cells treated with the vasopressin antagonist. d, The hazard function overlay (light line, before vasopressin; heavy line, after vasopressin) shows the reduction in doublet firing in a typical cell. e, Change in the number of doublets (intervals <10 ms), quantified for all doublet cells. f, Top: spike activity in a mitral cell, showing activity modulated by respiratory rhythm 5 s before and 5 s after odour. Middle and bottom: cumulative spikes from four tests during bursts before (middle) and after (bottom) vasopressin. g, Number of spikes 5 s before (white) and 5 s after (black) odour for the tests in f. h, Responses of another cell to odour (arrows) before, during and after artificial cerebrospinal fluid (ACSF) and vasopressin. i, Magnified instantaneous frequency records of the cell shown in h. j, Mean odour response in 16 cells tested with vasopressin, seven of which were also tested with ACSF, and in ten of which recordings were maintained long enough to observe recovery. Data shown, mean + s.e.m.; *P < 0.05, **P < 0.01.
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Under urethane anaesthesia, most mitral cells displayed patterned discharge comprising prolonged intermittent bursts of action potentials21 (burst duration, 159 ± 10 s; interburst time, 97 ± 13 s; intraburst firing rate, 6.4 ± 0.5 Hz; n = 94; Supplementary Fig. 3). Within these bursts, the firing activity is modulated by the respiratory rhythm. In addition, many mitral cells (57 of 94) displayed a bimodal interspike interval distribution, reflecting the frequent occurrence of spike doublets within bursts. Thus, within bursts, these cells fired at two distinct instantaneous frequencies: at 100–250 Hz (doublets; mean modal interspike interval, 3.2 ± 0.4 ms) and at ~50 Hz (mean modal interspike interval, 18 ± 1 ms). The doublets are noteworthy as it is believed that only high-frequency firing episodes are back-propagated into the distal dendrites22. Topical administration of vasopressin or the V1 receptor antagonist onto the exposed bulb dorsal to the recording site modified the electrical activity of mitral cells. Vasopressin reduced the proportion of time they were active, and particularly reduced doublet firing, whereas the antagonist had the opposite effect (P < 0.05, paired t-tests; Fig. 4c–e).
In 16 experiments, each involving a long recording from an identified mitral cell, we identified an odour to which that cell was particularly responsive, established the repeatability of that response in basal conditions and then retested the response to stimulation after topical application of vasopressin. In every case, the response to the odour was suppressed after vasopressin, whereas topical application of artificial cerebrospinal fluid had no effect on the responses of seven cells tested (Fig. 4f–j).
These findings suggest that vasopressin is a retrograde signal that filters activation of the mitral cells. Its effects may involve presynaptic modulation of noradrenaline or acetylcholine release, both of which are increased by retrodialysis of vasopressin in the olfactory bulbs of ewes23. Because this filtering is important for social recognition, it seems that the vasopressin release must depend on previous olfactory experience. In the hypothalamus, activity-dependent dendritic vasopressin release can be conditionally regulated (‘primed’) by recent experience12, 24; such a mechanism in the olfactory bulb may therefore mediate conditional changes in olfactory recognition.
Thus, the olfactory bulb contains vasopressin cells that process olfactory signals relevant to social discrimination, and dendritic vasopressin release may be involved in filtering out familiar signals. Genetic variations in brain vasopressin signalling are associated with differences in social behaviours in humans25, 26 as well as in animal models. We are not suggesting that social recognition in humans depends on olfactory signals; vasopressin affects social behaviour at many other sites as well as at the olfactory bulb27, 28, and in humans olfactory recognition probably has only a small role. However, these studies suggest a mechanism by which experience-dependent vasopressin release can facilitate social recognition, and this mechanism may be common to several sites of action.
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Methods Summary

Animal experimental procedures were conducted with regulatory approval and ethics committee approvals in the UK, Germany and Japan.
We processed brains immunocytochemically to detect cells expressing vasopressin, GFP, calbindin-D28k, calretinin, GABA, glutamate and V1a and V1b receptors, and by in situ hybridization to detect vasopressin mRNA and eGFP mRNA. Eleven eGFP rats were stereotaxically microinjected with the retrograde tracer Fluorogold at various sites to detect cells projecting from the olfactory bulb. Vasopressin content and potassium-stimulated release from olfactory bulb explants was measured by radioimmune assay.
To test effects on social discrimination, we bilaterally infused the V1 receptor antagonist or vehicle into the olfactory bulbs of adult rats15. A juvenile was introduced into the adult’s cage for 4 min and the duration of investigation by the adult was recorded; either 30 or 180 min later, the juvenile was reintroduced with another unfamiliar juvenile and the preference index ((time investigating unfamiliar juvenile)/(time investigating familiar juvenile + time investigating unfamiliar juvenile) × 100) was measured17. Olfactory habituation and dishabituation29 was tested by exposing rats to four 1-min trials separated by 10 min. During a fifth dishabituation trial, the rats were exposed to a novel stimulus. In rats injected with siRNA directed against V1a receptors (or control vectors), behaviours were tested 4, 8 and 16 d after injection.
For conditional ablation of vasopressin neurons, we used transgenic rats with a mutated human heparin-binding epidermal growth factor-like growth factor30 gene (HBEGF) under the control of vasopressin promoter. Diphtheria toxin was microinjected into the olfactory bulb in rats anaesthetized with tribromoethanol.
In urethane-anaesthetized rats, electrical activity of mitral cells was recorded before and after administration of vasopressin or V1 receptor antagonist onto a small exposure of the bulb. Cells were tested with odours applied for 2 s in an air stream directed at the nose. For in vitro electrophysiology, whole-cell current-clamp recordings were made from GFP-expressing cells in 300-μm horizontal olfactory bulb slices.
Full methods accompany this paper.
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