SD 4

Learning Objectives for Sexual Dimorphism and Behavior

Upon completion of this material, students should be able to:

• Illustrate the relevance of sexual dimorphism in mammalian brains and behavior.

• Describe the role of steroid hormone signaling in sex determination and behavior.

• Discuss neural pathways underlying sexual and parental behavior.

• Provide examples of neuropeptide regulation of social behavior.

Sexual Dimorphism in the Rodent Hypothalamus

Sexual dimorphism (the condition where the two sexes of the same species exhibit different characteristics beyond differences in sexual organs) is prominent in specific hypothalamic nuclei associated with sexual behaviors.

The Anteroventral Paraventricular Nucleus (AVPV)

• Function: Used for the control of cyclic ovulation.

• Composition: A collection of dopaminergic ($DA$) neurons.

• Dimorphism: In females, the volume and number of neurons are significantly higher ($\uparrow$) compared to males.

• Associated Markers: Kisspeptin ($Kiss$), Dopamine ($DA$), and $GABA/Glutamate$.

Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA)

• Dimorphism: In males, the volume and number of neurons are significantly higher ($\uparrow$) compared to females.

• Human Parallel: Similar sexual dimorphisms exist in the human anterior hypothalamus.

• Marker: Associated with Calbindin ($Calb$) expression.

Other Dimorphic Regions in Rodents

• Preoptic Area (POA): Males exhibit an increased number of dendritic spines ($\uparrow$).

• Bed Nucleus of the Stria Terminalis (BNST): Males show higher volume and neuron count ($\uparrow$), specifically associated with Calbindin ($Calb$).

• Ventral Part of Principal BNST Nucleus: Females exhibit higher volume and neuron count ($\uparrow$).

Case Study: Sexual Differentiation in the Spotted Hyena

The spotted hyena presents a unique case of sexual differentiation where typical mammalian roles are often reversed or altered.

Behavioral and Physical Characteristics

• Social Structure: Females ($\text{♀}$) are larger and more aggressive than males ($\text{♂}$), occupying the socially dominant position in groups.

• Anatomy: The female clitoris is enlarged, reaching the size of the male penis. It is used for:   - Urination   - Receiving semen   - Giving birth

Hormonal and Genetic Factors

• Placental Aromatase Deficiency: Spotted hyenas lack sufficient placental aromatase. Consequently, the mother produces androstenedione, leading to fetal exposure to high levels of androgens.

• Developmental Outcomes: Female pups demonstrate intense aggression, fighting siblings from birth.

• Brain Structure: Despite high androgen exposure, females retain a feminine SDN-POA and Spinal Nucleus of the Bulbocavernosus (SNB).

In Utero Anti-Androgen Treatment Effects

Research involving anti-androgen treatment in utero produced the following results:

• Limited Feminization of Male Fetuses: The penis developed into a clitoris, the prostate was absent, they developed a female-like bulbocavernosus muscle, and the SNB nucleus decreased ($\downarrow$).

• Limited ‘Hyperfeminization’ of Female Fetuses: Increased size and elasticity of the urogenital meatus (opening), decreased clitoris length, and increased glans diameter.

• Conclusion: While androgen exposure in utero explains some changes in female hyenas, it does not account for all observed sexual dimorphisms.

Neural Circuits and Pheromone-Induced Behaviors

Specific receptors and pathways regulate how rodents respond to social and sexual stimuli.

Sensory Channels and Required Components

• Pheromone Perception: Primary regions include the Medial Amygdala ($MeA$) and Bed Nucleus of the Stria Terminalis ($BNST$).

• CNGA2 (Cyclic Nucleotide Gated Channel Subunit Alpha 2): Essential for:   - Male mating behavior (sniffing, mounting, intromission).   - Male territorial aggression.   - Female maternal pup retrieval.

• TRPC2 (Transient Receptor Potential Cation Channel C2): Essential for:   - Male-specific courting (e.g., ultrasonic vocalization).   - Suppression of male courting behavior toward other males.

The Role of Aromatase+ BNST Neurons

• Identification of Sex: BNST neurons expressing Aromatase ($ext{Aromatase}^+$) utilize calcium ($Ca^{2+}$) sensing to identify the sex of an intruder.

• Optogenetics: These neurons can be photostimulated via Channelrhodopsin to observe behavioral changes during resident-intruder interactions.

Hormonal Regulation of Sexual and Parental Behavior

Ventromedial Hypothalamus (VMH) and Progesterone

• Lordosis: The VMH facilitates the lordosis reflex (back arching for mating receptivity) in female rats. This is measured by a lordosis reflex score in response to manual stimuli applied to the flank/perineal regions in estradiol-treated, ovariectomized females.

• PR+ Neurons: Progesterone Receptor ($ext{PR}^+$) neurons in the VMH regulate sexually dimorphic behaviors. Ablation of these neurons in females affects receptivity, while ablation in males affects the balance between sexual and aggressive behaviors.

• Esr1+ Neurons: Estrogen Receptor 1 ($ext{Esr1}^+$) neurons in the VMH respond to sexual experience. Calcium imaging shows that on Day 1 of sexual experience, activity levels start around $10-20\%$, but by Day 3, response to intruders increases, reflecting a refinement of the neural circuit.

Male vs. Female Sexual Pathways in Rodents

• Male Pathway: Vomeronasal organ detects pheromones from receptive females $ightarrow$ Medial Amygdala ($MeA$) $ightarrow$ Medial PreOptic Area ($MPOA$). Circulating testosterone is converted to estrogens at these sites. Output flows to the basal ganglia, ventral midbrain, brainstem, and spinal cord ($L5$) to facilitate erection and ejaculation.

• Female Pathway: Estrogens affect the $MPOA$ and Ventromedial Hypothalamus ($VMH$). Estrogens induce progesterone receptors. Signal flows through the Periaqueductal Gray ($PAG$) $ightarrow$ Medullary reticular formation $ightarrow$ Reticulospinal tract $ightarrow$ Spinal cord ($L1-L6$) to facilitate lordosis.

Parental Behavior and Medial PreOptic Area (MPOA)

• Pup Retrieval: A learned or hormonal behavior. Lactating mothers show significantly faster retrieval times than experienced virgin mice across multiple pup trials.

• Galanin+ Neurons: Neurons expressing Galanin ($ext{Gal}^+$) in the MPOA are critical for parental behavior. This circuit involves connections between the $MeA$, $MPOA$, $VTA$ (Ventral Tegmental Area), and $PAG$.

Neuropeptides and Pair Bonding in Voles

Social structure in voles is heavily influenced by the distribution of neuropeptide receptors.

• Prairie Voles: Monogamous. They exhibit high levels of Vasopressin and Oxytocin receptors.

• Promiscuous Voles: Notable for different receptor distributions in the brain.

• Male Bonding: Infusion of Vasopressin into the Ventral Pallidum ($VP$) of male prairie voles is sufficient to establish pair bonding even without mating.

• Female Bonding: Infusion of Oxytocin into the Nucleus Accumbens ($NAcc$) is linked to partner preference.

• Preference Test: In studies where males were infused with Vasopressin vs. a vehicle control (artificial cerebrospinal fluid), the Vasopressin-infused males chose their partner over a novel female significantly more often.

Human Brain and Cognition: Sex Differences

Human Cognitive and Motor Ability Differences (Hines, 2010)

Brain Activation and Romance

• Activation: Pictures of a "beloved" relative to an acquaintance activate the Ventral Tegmental Area ($VTA$) and Caudate Nucleus.

• Deactivation: Specific brain areas are deactivated when viewing pictures of one's children or romantic partners.

Technical Abbreviations

• AOB: Accessory Olfactory Bulb

• AR: Androgen Receptor

• ARC: Arcuate Nucleus

• AVPV: Anteroventral Periventricular Nucleus

• BNST: Bed Nucleus of the Stria Terminalis

• Calb: Calbindin

• CNGA2: Cyclic Nucleotide Gated channel subunit Alpha 2

• CP: Caudate Putamen

• ER: Estrogen Receptor

• GnRH: Gonadotropin-Releasing Hormone

• Kiss: Kisspeptin

• LS: Lateral Septal nuclei

• MeA: Medial Amygdala

• MPOA: Medial PreOptic Area

• NAcc: Nucleus Accumbens

• PAG: PeriAqueductal Gray

• PFC: PreFrontal Cortex

• PR: Progesterone Receptor

• Rt: Nucleus rotundus

• SNB: Spinal Nucleus of the Bulbocavernosus

• TRPC2: Transient Receptor Potential cation channel C2

• VMH: VentroMedial Hypothalamus

• VNO: VomeroNasal Organ

• VP: Ventral Pallidum

• VTA: Ventral Tegmental Area