We previously reported that periovulatory odors, an important sexual stimulus for male marmosets, produced activation of the MPOA and anterior hypothalamus two areas critical for male precopulatory and copulatory behavior (6
). Here we demonstrate both activation and deactivation of multiple brain areas in response to periovulatory and OVX odors compared to vehicle control odors. Many areas showing BOLD activation to sexually arousing stimuli in marmosets overlap with comparable areas in humans (using both PET and fMRI), although the stimuli are quite different (odors vs. visual and auditory stimuli). Both humans and marmosets show activation in the cingulate cortex, temporal cortex, insula, caudate, hypothalamus, and cerebellum (9
The most notable difference between humans and marmosets is the absence of amygdala activation in marmosets. The amygdaloid complex appears critical in sexual arousal and motivation. Marmosets showed both significant activation and deactivation of the amygdala to both periovulatory and OVX odors compared to vehicle control, but no significant difference between odors. The most plausible explanation is inadequate spatial resolution. The amygdaloid complex has over 20 discrete nuclear areas, and only a few may be involved in processing sexually arousing stimuli. We included the entire amygdala in our ROI (see ), so potentially significant changes in both positive and negative BOLD to each stimulus may have occurred in different individual nuclei.
Interestingly, the cerebellum showed robust activation in both marmosets and humans to sexually arousing stimuli. PET and fMRI studies report increased cerebellar activity in response to positive and negative emotional stimuli (15
). The cerebellum has extensive neural connections with the somatosensory cortex and association areas, i.e., prefrontal, temporal, and cingulate cortices, as well as the hypothalamus (17
). Beauregard et al (13
) suggested the cerebellum might be involved in the somatic experience associated with sexual arousal.
The brain areas activated by sexually provocative cues in marmosets and humans represent not only a common circuit for sexual arousal and motivation, but also are part of a larger appetitive or approach motivational system (18
). Physiological and behavioral data on marmoset reproductive activity support this notion since odors from ovulating marmosets induce approach behavior in males. Presentation of sensory stimuli with positive affective valence activated the prefrontal cortex, temporal cortex, somatosensory cortex, insula, cingulate, and amygdala in healthy human subjects (16
One of the most interesting results was the “mirror image” of brain activity in marmosets exposed to periovulatory versus OVX odors. Several areas associated with arousal and sexual motivation: temporal cortex, MPOA, cingulate, insula, caudate, and cerebellum, showed significant deactivation in response to the OVX odor relative to vehicle control. OVX odors may have a more negative emotional valence, inhibiting appetitive motivation. However, marmoset males copulate with ovariectomized females when housed together as a bonded pair (21
). Possibly the olfactory cues of reproductive status are most important to a male evaluating his response to an unfamiliar female, whereas with a pair-bonded mate learned responses to other features override the olfactory cues. If this is true, then we should find different responses to cues from an unfamiliar female versus learned cues from a mate. This provides a way to separate the biological and experiential aspects of sexual response. Imaging data from non-human primates has heuristic value in interpreting and understanding brain images of human sexual responses.
In human PET studies, changes in brain activity to negatively valenced emotions produce increased activation in left inferior frontal, left anterior cingulate, and left temporal pole regions (22
). With all negative emotional stimuli, the left temporal cortex is activated. We found little lateralization of odor-induced brain activity in male marmosets except the left temporal cortex. OVX odors increased activity in the left temporal cortex, suggesting that this area, as in humans, may be involved in processing negative emotional stimuli.
Both periovulatory and OVX odors produced both positive and negative BOLD signal in many of the same brain areas suggesting that positive and negative motivational systems reside in the same areas. Lane et al (16
) used PET in female subjects presented with pleasant and unpleasant stimuli and discovered a consistent overlap for each motivational system in the medial insular cortex and prefrontal cortex. In marmosets, positive stimuli (periovulatory odors), and presumably negative stimuli (OVX odors), consistently increased BOLD signal in the same brain areas even though there was significantly more activation with the periovulatory odors in most areas. Only three of 21 brain areas showed significant differences in positive versus negative BOLD to periovulatory odors.
These data suggest a common neuroanatomical circuit for sexual arousal and sexual motivation that may be affected by other regions weighted for context-dependent approach and withdrawal responses. The periaqueductal gray (PAG) and MPOA are two areas where the number of positive BOLD voxels significantly exceeded the number of negative BOLD voxels during presentation of periovulatory odors. These sites might be selectively weighted toward approach behavior in the context of sexual arousal and motivation. The MPOA is critical for the organization and initiation of male sexual behavior (23
). Activation of the MPOA facilitates sexual behavior, while lesions prevent copulatory behavior in every species studied. In rats the MPOA has dense reciprocal connections to the PAG (24
). In turn, the PAG has inputs to the nucleus paragigantocellularis (nPGi) whose connections to the spinal cord control male reproductive reflexes (25
). This MPOA–PAG–nPGi neural circuit may be essential in activation of male sexual reflexes (25
Conversely, the raphe nucleus was the only site showing a significant decrease in positive BOLD voxels in response to periovulatory odors and the only site with a significant increase in positive bold voxels to OVX odors. The raphe may be weighing toward avoidance behavior in the context of sexual arousal and motivation. The raphe is the primary source of serotoninergic innervation of the forebrain and is considered part of a behavioral inhibition system. Electrical stimulation of the raphe elicits freezing behavior (26
), and blocking raphe activity reduces the inhibitory effect of conditioned aversive stimuli on bar pressing (27
). Disrupting serotoninergic neurotransmission from the raphe promotes feeding (28
) and enhances male sexual activity (29
). Periovulatory odors may suppress raphe activity, disinhibiting sexual behavior, whereas OVX odors may enhance raphe activity, suppressing sexual approach behavior.
The robust negative BOLD signal observed is interpreted as brain deactivation. Use of the phrase “inhibition of brain activity” would be incorrect, because synaptic inhibition in the form of inhibitory postsynaptic potentials is an active process accompanied by enhanced oxidative metabolism. Brain deactivation suggests reduced synaptic and neuronal activity without specifying a biophysical mechanism. None of the human fMRI studies examining sexual arousal in males presented data on negative BOLD signal. However, Bartels and Zeki (30
), imaging romantic love in young women, discussed widespread deactivation in the prefrontal, parietal, and temporal cortices concomitant with enhanced BOLD signal in the insula, cingulate, caudate, and putamen. The occurrence of negative BOLD signal is often recognized as brief “dips” and “troughs” in blood flow at the beginning and end of a stimulus, but not normally associated with brain deactivation (31
). However, examples of robust negative BOLD signal have been found in the visual cortex, presumably reflecting suppression of neuronal and synaptic activity (36
). For example, activation of the visual cortex in children and adults was studied using BOLD and arterial water spin labeling to assess regional Cerebral Blood Flow (rCBF). Adults showed both an increase in BOLD and rCBF to visual stimulation. However, children showed a decrease in BOLD concomitant with a decrease in rCBF (37
This study shows that fMRI is a feasible method for identifying neuroanatomical circuits involved in sexual arousal in conscious marmoset monkeys. Data from marmosets appear to translate to human sexual arousal and motivation since many of the neuroanatomical areas identified previously in human imaging studies overlap with those reported here. The circuitry is part of a general appetitive circuit for positively valenced emotional stimuli. The virtue of the marmoset model is the ability to control precisely the developmental and social history and to carry out conditioning studies not possible in humans.