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Different Subsets of Preoptic Neurons for Proceptive and Receptive Components of Female Rat Sexual Behavior

Yasuo Sakuma

CONTENTS I. Introduction II. Proceptive Behavior in the Female Rat III. Neuronal Activity in Conscious Rats IV. Neuronal Activity during Sexual Behavior V. Preoptic Neuronal Activity and Sexual Motivation VI. Conclusions VII. Acknowledgments References

I. Introduction
Sexual behavior in the laboratory rat is characterized by its dependence on circulating titers of sex hormones and sexual dimorphism. Over the past few decades, these attributes have been used successfully to identify neural substrates for various components of female and male rat sexual behavior. Earlier contributions centered about the detailed description of the components of sexual behavior in each sex and the identity of effective sex hormones that regulate them. Thus, in the female rat, proceptive and receptive components have been distinguished. The lordosis reex, an estrogen-sensitive postural reex with a dorsiexion of the vertebral column, is by far the most closely scrutinized among the receptive components of female rat sexual behavior. The neural circuitry for the lordosis reex, which includes estrogen-sensitive facilitatory and inhibitory components, has been identied.

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However, only anecdotal knowledge is available concerning brain mechanisms for anticipatory and motivational aspects of female rat sexual behavior, which has been collectively termed proceptive or solicitatory components.

II. Proceptive Behavior in the Female Rat

In the rat, sexual interactions are initiated and paced by females in estrus through patterns of approach toward and withdrawal from sexually active males.1 Highly estrous females display precopulatory hopping, darting, and ear wiggling to provoke males to initiate mounting, which constitute proceptive behavior. Basal forebrain structures, that include the preoptic area (POA), substantia innominata, and accumbens, are often implicated in the regulation of motivated behaviors.2,3 Female rats with basal forebrain lesions spend less time in the vicinity of males than the nonlesioned controls4 and display an unusually high incidence of rejection behavior in response to attempted mounts by male rats.5 POA neurons, and not axons of passage, are involved in this effect, because POA lesions generated by an excitotoxin had a similar effect.6 An increased locomotion in females in estrus, which depends apparently on estrogen-sensitive POA projections7 to the midbrain locomotor region,3,8 has been considered to embody enhanced sexual motivation.9-11 The fact that females continue to exhibit increased locomotion and other proceptive behaviors whenever males dismount without intromission suggests the consummatory value of intromission.12 Estrogen-sensitive POA projections extend not only to the midbrain locomotor region7 but also to the ventral tegmental area.13 The ventral tegmental area is the origin of dopaminergic projections toward the forebrain and has also been implicated in motivated behaviors.14,15 Transient activation of presumed dopaminergic neurons in the midbrain ventral tegmental area has been recorded in rats engaging in motivational behavior.16 During both appetitive and consummatory phases of male rat sexual behavior, dopamine release increases in the POA and other forebrain structures.17 In all likelihood, the activation of the ascending dopaminergic projection is responsible for the increased dopamine release in the forebrain.18 Dopamine has been implicated in the regulation of consummatory components of female rat sexual behavior.19,20 Indeed, dopamine receptor stimulation in the forebrain has been associated with either increased locomotion21 or sexual motivation.22 Therefore, as the origin of the descending effects on locomotor activation and as a target of ascending dopaminergic projection, the POA seems to occupy a pivotal point in the regulation of sexual motivation in the female rat. However, few studies have attempted to relate neuronal activity in the POA of conscious, unrestrained female rats to events with any signicance in sexual motivation. In the present study, we implanted a bundle of wire electrodes in the POA to record single unit activities from female rats engaging in sexual interactions.
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III. Neuronal Activity in Conscious Rats

Single unit activities were recorded from the POA of conscious female rats engaging in sexual interactions. For this purpose, microwire electrodes were implanted in advance under pentobarbital anesthesia in the ovariectomized female rats. Prior to recordings, the animals received a combination of estrogen and progesterone to make them highly estrous. We followed Onos method23 for recordings, modied from the original design by Palmer.24 Briey, an 8-strand bundle of Teon-coated 25-m thick, platinum-iridium wire was passed through a 23-gauge stainless steel tube and secured in position by isobutyl cyanoacrylate glue. The wires protruding from the tube were cut with sharp scissors to make the recording area and fastened together with polyethylene glycol to allow penetration into the brain. Once implanted in the brain, the polyethylene glycol dissolved into the extracellular uid, and the wires split free. The other end of each wire was connected to 10 pin miniature IC sockets. For recording, an impedance-matching amplier with a 500-M input impedance was attached directly to the IC socket on the skull. The outputs of the unity-gain amplier were fed via a lownoise cable to conventional ampliers. Both on-line and off-line analyses depended on a Concurrent MC-7000 computer for multiple channel data acquisition, display, and storage. The heterogeneity of the POA made the identication of recordings from single neurons essential. Three stringent criteria were used to establish that recordings were made from single neurons. The identity of single neurons depended on a high signal-to-noise ratio and stable waveform. An auto-correlogram of rings in any single neuron showed a reduced probability of ring at intervals that reect refractory periods of each neuron. Behavioral observation and videotape recordings were made under a dim red light with Sony CCD cameras and VCRs. Female sexual behavior was punctuated by several consecutive events that occurred either spontaneously or in response to stimuli from the male partner. The events included (1) the initiation of proceptive locomotion, (2) mounting by male partners with or without intromission, (3) the commencement of the lordosis reex, and (4) dismounting by the male. Concurrent recordings of single-unit activity and behavior were accomplished from 31 neurons in 25 estrous females during the entire course of sexual interaction that encompassed both proceptive and receptive components. Waveforms of recorded potentials were either positive-negative biphasic or negativepositive-negative triphasic. Biphasic potentials had peak-to-peak amplitudes no less than 200 V. Overall duration of the potential, which spanned both positive and negative components, ranged 0.4 to 2.1 msec. Triphasic potentials were smaller in the amplitude (120 to 200 V) and lasted longer (up to 3.1 msec) than biphasic potentials.

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FIGURE 20.1 Temporal relationship between neuronal activity and sexual behavior in rate-meter and ethogram charts. The activity in 14 among 31 preoptic neurons was related to bouts of sexual interactions. Represented are four types of neurons (Types 1 to 4), which were associated with different events in sexual behavior in peri-event histograms (see results). Abbreviations in ethogram chart: S, solicitatory locomotion; M, mounting; I, intromission. Behavioral observation and recordings of neuronal activity lasted until female rats received ejaculation (E).
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IV. Neuronal Activity during Sexual Behavior

Based on rate-meter histograms, the activity in 14 of 31 neurons was connected with bouts of sexual interactions with a male partner (Figure 20.1). The 14 neurons had an overall discharge rate that ranged from 3.5 to 40.4 Hz (overall mean 10.3 Hz). Further identication of temporal relationships between the activity of the 14 neurons and the initiation of particular behavioral events depended on peri-event histograms. Solicitation, mounting by the male, lordosis, and dismounting were identied on video frames and used as the reference events. In peri-event histograms, changes in neuronal activities occurred prior to or in connection with behavioral events. It was noted that the activity in each neuron was related to a single behavioral event. Mutual dependence between events, which occurred in succession in a xed order, made it appear that the activity in some neurons changed in association with several events; comparisons between peri-event histograms for different references dismissed the possibility. Four different types of changes in neuronal activity were distinguished in peri-event histograms. Type 1: four neurons increased their ring rate when female rats initiated proceptive locomotion; Type 2: another four showed signs of brief activation when females were mounted by males; Type 3: four neurons were activated in response to intromission, and Type 4: the remaining two were inhibited prior to and throughout the display of lordosis reex. Electrolytic lesions positively identied recording sites of Types 1 to 3 neurons mainly in the transitional region between the medial and lateral POAs. Neurons that red independently of sexual interactions were also in this region, and, in addition, scattered into surrounding areas that included the bed nucleus of the stria terminalis, medial part of the substantia innominata, and the anterior hypothalamus. Two Type 4 neurons were found more medially than the others in the medial POA (Figure 20.2). The effects of dopamine receptor blockade by systemic injection of pimozide were observed in three neurons. Within 15 minutes after the injection, pimozide diminished neuronal discharge in Type 1 neurons (n = 2) and abolished proceptive behavior altogether, without disrupting the ability of female rats to show the lordosis reex.

V. Preoptic Neuronal Activity and Sexual Motivation

In the present study, at least four types of POA neurons (Types 1 to 4) were distinguished, based on their activities during sexual interactions with conspecic males. Specically, neurons classied as Type 1 increased their discharge rates during solicitatory locomotion. The increased discharge of Type 1 neurons was terminated altogether with the solicitatory behavior when males accomplished intromission. Neuronal activation preceded the re-emergence of
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CC

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VL LS CP

LS

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FIGURE 20.2 Locations of different types of neurons in frontal sections of the rat forebrain. Solid circles, Type 1; solid squares, Type 2; diamonds, Type 3; and triangles, Type 4, Open squares, neurons that red independently of sexual interactions. Horizontal bar: 1 mm. Numbers in each panel, distances from the center of the ear bars in mm. Abbreviations: aco, anterior commissure; AHA, anterior hypothalamus; BST, bed nucleus of stria terminalis; cc, corpus callosum; CP, caudate putamen; fx, fornix; GP, globus pallidus; int, internal capsule; lPOA and mPOA, lateral and medial preoptic areas; LS and MS, lateral and medial septal areas; NDB, nucleus of diagonal band of Broca; och, optic chiasm; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SI, substantia innominata; sm, stria medullaris; SO, supraoptic nucleus; st, stria terminalis; V3, third ventricle; VL, lateral ventricle.

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solicitatory locomotion. Both the neuronal activation and the display of solicitatory behavior persisted when males did not accomplish intromission. Male mounts without intromissions sufced to excite Type 2 neurons. Another group of neurons (Type 3) showed short bursts only when intromission occurred. The activity of Type 4 neurons was diminished prior to and during the entire period of the display of the lordosis posture. Types 2 and 3 neurons were activated by somatosensory stimulation. The inhibitory effect of intromission on Type 1 neurons implicates the consummatory value of this particular behavior. The inhibition of Type 4 neurons during the display of the lordosis reex (Type 4) agrees with predictions based on behavioral results.6,25 Types 1 to 3 neurons were recorded from the transitional zone between the medial and lateral POAs, which approximated the so-called preoptic locomotor region.26 The site overlapped the core of the distribution of retrogradely labeled neurons after injections of a uorescent marker into the midbrain locomotor region.3 Although neurons that change their activity during locomotion in general are scattered throughout the basal forebrain,27 estrogen-excitable POA projections7 originate here to innervate the midbrain locomotor region.8 The estrogen-induced increase in the locomotor activity28 has been attributed to the activation of this system. In contrast, Type 4 neurons were recorded far medially in the core of the medial POA. These observations corroborate the results of recording studies in anesthetized rats indicating that neurons with a particular function group together in specic subdivisions of the POA.29 The interpretation that the activity of the Type 1 neurons reects motivational states of the female rats in estrus is reinforced by the difference in the prole of activity of Type 1 neurons prior to mounting with intromission. This also corroborates the behavioral inference that the female rat determines pacing and intromission in sexual interactions,1 so that sensory information relevant to intromission could have a consummatory value for sexual motivation. In fact, intromission during copulation correlates negatively with subsequent appetitive sexual behavior.1,12 Instrumental responding analysis has shown that females that received mounts with intromission are slower to respond subsequently to males than females that received mounts without intromission.30 Visceral or somatosensory inputs from the vagina may be responsible for short bursts in response to intromission in Type 3 neurons. Two ascending pathways, one via the pelvic nerve31 and the other via the vagal afferents,32 have been shown to contribute to the ascending neural transmission following mechanical stimulation of the vagina that simulated intromission. Rapid activation in multiple or cumulative neuronal activities in the POA has been reported to follow vagino-cervical probing in the estrogen-treated ovariectomized rat.33,34 Comparison of such observations with the present results should be made, given the heterogeneity of the POA neurons. Indeed, some earlier studies report an inhibitory effect of vagino-cervical stimulation on neuronal activities in the POA.35
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Because mounts by male partners provide physiologically appropriate stimuli for the lordosis reex, the mount-induced activation in Type 2 neurons could reect sensory input for the lordosis reex, but efferent POA neurons with axons to the ventral tegmental area constitute the inhibitory circuitry for the lordosis reex.25 Experiments under anesthesia showed that the number of neurons excited by ank stimulation, which is pertinent to somatosensory stimuli given by male mounts, decreased after estrogen treatment.36 Such reductions would agree with behavioral studies if the recordings were made from the inhibitory POA efferents of the lordosis reex. It could therefore be possible that the observed activation relates to the termination of locomotion that precedes the lordosis reex,36 rather than the induction of the reex itself. Indeed, Type 4 neurons in this study behaved exactly as if they inhibit the execution of the lordosis reex: their discharge subdued prior to and during the display of the reex. Such a depressed activity during lordosis has been also recorded from the limbic structures in estradiol-primed hamsters.37 Present results provide clues to interpreting the results of recording studies under anesthesia and c-Fos induction studies. The general lack of responses of POA neurons in ovariectomized, estrogen-treated rats to somatosensory stimuli in acute recording studies,13,36 may be at least partially due to anesthesia. The expression of the immediate-early gene c-Fos has been used widely to identify populations of neurons in diverse structures in the female rat brain that are activated during copulatory interactions (reviewed in reference 38). The method has an advantage in surveying neuronal activation over wide regions of the brain. Nevertheless, in general, c-Fos induction requires intensive, repetitive stimuli and lacks the time resolution to relate neuronal activation to individual events in female rat sexual behavior. c-Fos immunocytochemistry detects neuronal inhibition only when proper controls are available.39 Amounts of copulatory stimuli needed to induce c-Fos in the female rat brain have been examined in detail.38,40 For the consistent induction of c-Fos or its mRNA, female rats were either subjected to powerful copulatory stimuli that amount to 50 mounts with intromission and 5 ejaculations, or intensive manual41-43 or mechanical44 vagino-cervical probing. Such stimuli induces c-Fos in neurons in the POA, hypothalamus, limbic and midbrain regions. In addition, neurons in the cerebral cortex and striatum express c-Fos protein in response to vaginal probing,45 suggesting that there is sensorimotor activation by the stimulation. Indeed, the effect is diminished by transection of the pelvic nerve,46 a major sensory afferent path for vaginocervical stimulation,31 so that neuronal activation identied by c-Fos induction may, in large part, reect the somatosensory or viscerosensory activation discussed by Pfaus and Heeb.47 Given that intensive manual ank stimulation produces a much smaller induction of c-Fos than vagino-cervical probing,38 the short bursts in Type 2 neurons in response to mounting without intromission in the present study would have escaped detection by c-Fos immunocytochemistry. Similar short
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bursts in Type 3 neurons caused by intromission would also be beyond detection. Transient changes in neuronal activity in other groups of neurons, punctuated by behavioral events, would not be identied because such changes often included inhibitory components. Together with the different topography within the POA, neuronal activity associated with behavioral events or motivational states in the present study were likely made from different populations of POA neurons that have been identied by c-Fos expression. Dopamine receptor blockade by pimozide diminished proceptivity and neuronal activity in Type 1 neurons. The ascending dopaminergic projections toward the forebrain, which originate in the midbrain ventral tegmental area, have been implicated in motivated behaviors.48 It is also known that the incerto-hypothalamic dopaminergic projection originates in the periventricular hypothalamus and medial zona incerta,49 but the latter intradiencephalic system with short axons has been implicated in the control of gonadotropin secretion, rather than that of motivated behaviors. In presumed dopaminergic neurons in the ventral tegmental area of conscious monkeys50 and rats,16 strong neuronal activation takes place at the initiation of motivated behaviors. As in Type 1 neurons in the present study, these neurons cease ring once action is initiated.16 Systemic application of pimozide apparently excites POA neurons through D1 receptor20 to facilitate sexual behavior.51 Indeed, certain POA neurons are excited by either microiontophoresis of dopamine on their soma or electrical stimulation of their ventral tegmental efferents.52 Studies employing microdialysis53 or in vivo voltammetry22 have shown a global increase in dopamine content in the POA and other forebrain structures during sexual interactions in the female rat. Dopaminergic efferents of the ventral tegmental area might have contributed to the activation of Type 1 neurons in the present study. For other types of POA neurons in the present study, the origins of neural inputs that modied their activity are beyond such conjecture. Although limited in number, neurons in the septum, amygdala, and other limbic structures of estradiolprimed hamsters showed ring associated with orienting, snifng, and rearing.37 In addition to afferents from many forebrain and brain stem structures, the POA contains local interneurons that presumably form local circuits.54 In the POA, many neurotransmitters or neuromodulators other than dopamine have been associated with certain events underlying female rat sexual behavior. Some of them have been shown to affect both neuronal activity and components of female rat sexual behavior.55 For example, GnRHinduced receptivity may depend on the activation of POA neurons.56,57 Opiates in the POA may also play a role in the modication of sexual behavior.58,59 It has been suggested that the inhibitory neurotransmitter aminobutyric acid (GABA) is important in the estrogen-dependent control of GnRH.60 GABAergic synaptic contacts are widespread in the medial POA,61 but the paucity of the data in past studies on the identity of neurons from which recordings were made complicates interpretation. Discrepancies in the results of behavioral studies that employed either electrical or chemical stimulation62 may also be due to the activation of separate subsets of neurons.
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VI. Conclusions
Single neuron activities in the POA of female rats in estrus changed in association with the motivational state and sensorimotor events during sexual interactions. Most changes were subtle and transitory, and would be beyond detection by other methods which yield average values over minutes or hours. The patterns of event-related changes in neural activity in the POA were unique in their time course. Whereas the activity of certain neurons embodied the motivational states of the animal, some neurons responded specically to certain somatosensory inputs, and in others the activity can be associated with the execution of a particular component of female rat sexual behavior.

VII. Acknowledgments
Supported by grants-in-aid for scientic research from the Japanese Ministry of Education, Science, Sports, and Culture (MESSC), Nos. 06680796 and 10480227.

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