Major depression is a chronic illness with a high prevalence and is a major component of disease burden. Depressive disorders were the second leading cause of years lived with disability in 2010 in Canada, the United States and globally.1,2 When depression-related deaths due to suicide and stroke are considered, depression has the third highest global burden of disease.3 Major depression is growing in overall disease burden in Canada and around the world; it is predicted to be the leading cause of disease burden by 2030, and it is already the leading cause in women worldwide.4 Between 1990 and 2010 in Canada, major depressive disorder showed a 75% increase in disability-adjusted life years,1 the second greatest increase in prevalence after Alzheimer disease; in comparison, the increase in the United States was 43%.2 At the same time, the female:male ratio of global disability from major depression remained unchanged at 1.7:1. Although differences in socioeconomic factors, including abuse, education and income, may impact the higher rate of depression in women,5 this editorial focuses on biological contributors that are experimentally tractable and may help to understand how and why depression is more prevalent in women and lead to better treatments.

The prevalence of major depression is higher in women than in men;6,7 in 2010 its global annual prevalence was 5.5% and 3.2%, respectively, representing a 1.7-fold greater incidence in women.1,8 In Canada, the prevalence was 5.0% in women and 2.9% in men in 2002 (1.7-fold greater incidence in women) and increased to 5.8% and 3.6%, respectively, in 2012 (1.6-fold greater incidence in women).9,10 The finding of similar female:male prevalence ratios in developed countries and globally suggests that the differential risk may primarily stem from biological sex differences and depend less on race, culture, diet, education and numerous other potentially confounding social and economic factors. There is no clear evidence that the rate of depression is greater in countries where women have markedly lower socioeconomic status than men than in countries where there may be more equal footing.5 Depression is more than twice as prevalent in young women than men (ages 14–25 yr), but this ratio decreases with age.9,10 Indeed, starting at puberty, young women are at the greatest risk for major depression and mental disorders globally.1 Importantly, before puberty, girls and boys have similar rates of depression; the rate is perhaps even higher for boys.6 At ages older than 65 years, both men and women show a decline in depression rates, and the prevalence becomes similar between them.9,11 A greater prevalence of depression in women is also reflected in prescriptions for antidepressant medications. In Canada between 2007 and 2011, antidepressants were prescribed more than twice as often to women than men (9.3% v. 4.2% in patients aged 25–44 yr, 2.2-fold; 17.2% v. 8.2% in patients aged 45–64 yr, 2.1-fold).12 The age discrepancy between the peaks in the prevalence of depression (age 14–25 yr)10 and the prevalence of antidepressant use (> 45 yr) suggests that young adults with depression may not always receive antidepressant treatment until many years after the onset of illness. This delay in medication could contribute to the higher rates of depression during adolescence and young adulthood and would be important to study more rigorously comparing treated and nontreated cohorts. Delay in antidepressant treatment might reflect stigma or underdiagnosis in adolescence. New antistigma and educational programs targeted to youth may help reduce depression in this age group.13

Why then is depression more prevalent among women? The triggers for depression appear to differ, with women more often presenting with internalizing symptoms and men presenting with externalizing symptoms.14 For example, in a study of dizygotic twins, women displayed more sensitivity to interpersonal relationships, whereas men displayed more sensitivity to external career and goal-oriented factors.15 Women also experience specific forms of depression-related illness, including premenstrual dysphoric disorder, postpartum depression and postmenopausal depression and anxiety, that are associated with changes in ovarian hormones and could contribute to the increased prevalence in women. However, the underlying mechanisms remain unclear; thus, treatments specific to women have not been developed.

The fact that increased prevalence of depression correlates with hormonal changes in women, particularly during puberty, prior to menstruation, following pregnancy and at perimenopause, suggests that female hormonal fluctuations may be a trigger for depression. However, most preclinical studies focus on males to avoid variability in behaviour that may be associated with the menstrual cycle. Nevertheless, primate and rodent studies consistently implicate a role for female hormones, such as estrogen, in depression. Perhaps the most naturalistic depression studies to date to address the role of female hormones involved small groups (n = 4–5) of female macaque primates that formed lifelong social hierarchies with dominant and subordinate females. The latter showed a depression-like phenotype16 that has been associated with a brain-wide decrease in serotonin 1A (5-HT1A) receptor levels and decreased hippocampal volume.17,18 Interestingly, the reduced hippocampal volume was more extensive in postmenopausal monkeys than in ovarian-intact monkeys, suggesting that ovarian function may be protective. Consistent with this finding, the risk of depression appears to increase during the perimenopausal transition.19 Emerging evidence indicates that hormone replacement therapy, particularly during the perimenopausal period, can be effective in the prevention of postmenopausal depression in women.20 Another study involving female macaques examined relocation stress–sensitive alterations in their menstrual cycles and showed depression-related behaviours and reductions in the function of the brain serotonin system.21 In this light, a recent study has indicated that women who reported using an oral contraceptive (especially monophasic contraceptives) showed reduced rates of major depression and anxiety compared with nonusers,22 suggesting that moderating the cycling of estrogen may be protective. Taken together these studies suggest that estrogen may have a protective effect on the pathology that underlies depression and that decreases in estrogen may increase the risk for depression.

Why then do men, who lack systemic estrogen, have lower rates of depression than women? Accumulating research has shown that in the male brain testosterone is converted into estrogen by endogenous aromatase (CYP19). Estrogen could mediate protective actions through estrogen receptors expressed throughout the male brain (especially estrogen receptor β).23 In addition, the presence of androgen receptors in men may confer protection, for example in hippocampal neurons.24 Since testosterone does not cycle in men as estrogen does in women, there may be a more consistent protection in men. However, men also have sexually dimorphic brain nuclei, particularly in the hypothalamus, so the lower prevalence of depression in men is probably more complex owing not only to hormonal differences, but also to developmental differences in brain circuitry.23

In the most fundamental terms, the sex difference in depression rates reflects the fact the men and women are different: women have 2 copies of the X chromosome, while men have 1 copy each of X and Y chromosomes, the latter not being present in women. Understanding how this fundamental genetic difference confers sexual differences in predisposition to mental illness is a complex, multilevel puzzle that remains to be clarified. Society-driven risk factors for depression in women likely have a biological origin, such as differences in physical strength and personality traits, leading to a higher prevalence of depression in women. Perhaps what needs to change are social attitudes to promote equality; yet, this has been occurring in the West and has yielded no clear change in the female:male depression ratio.5 However, despite this complexity, recent evidence suggests that biological factors, such as the variation in ovarian hormone levels and particularly decreases in estrogen, may contribute to the increased prevalence of depression and anxiety in women and that strategies to mitigate decreases in estrogen levels may be protective. Identifying ligands that more specifically target the brain (e.g., estrogen receptor-β-selective ligands) may protect from depression but avoid adverse effects of estrogen therapy.25

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Why is depression more prevalent in women

Relationships between Pupil Diameter and Neuronal Activity in the Locus Coeruleus, Colliculi, and Cingulate Cortex.

Ascending projections from the dorsal raphe nucleus (DR) were examined in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). The majority of labeled fibers from the DR ascended through the forebrain within the medial forebrain bundle. DR fibers were found to terminate heavily in several subcortical as well as cortical sites. The following subcortical nuclei receive dense projections from the DR: ventral regions of the midbrain central gray including the 'supraoculomotor central gray' region, the ventral tegmental area, the substantia nigra-pars compacta, midline and intralaminar nuclei of the thalamus including the posterior paraventricular, the parafascicular, reuniens, rhomboid, intermediodorsal/mediodorsal, and central medial thalamic nuclei, the central, lateral and basolateral nuclei of the amygdala, posteromedial regions of the striatum, the bed nucleus of the stria terminalis, the lateral septal nucleus, the lateral preoptic area, the substantia innominata, the magnocellular preoptic nucleus, the endopiriform nucleus, and the ventral pallidum. The following subcortical nuclei receive moderately dense projections from the DR: the median raphe nucleus, the midbrain reticular formation, the cuneiform/pedunculopontine tegmental area, the retrorubral nucleus, the supramammillary nucleus, the lateral hypothalamus, the paracentral and central lateral intralaminar nuclei of the thalamus, the globus pallidus, the medial preoptic area, the vertical and horizontal limbs of the diagonal band nuclei, the claustrum, the nucleus accumbens, and the olfactory tubercle. The piriform, insular and frontal cortices receive dense projections from the DR; the occipital, entorhinal, perirhinal, frontal orbital, anterior cingulate, and infralimbic cortices, as well as the hippocampal formation, receive moderately dense projections from the DR. Some notable differences were observed in projections from the caudal DR and the rostral DR. For example, the hippocampal formation receives moderately dense projections from the caudal DR and essentially none from the rostral DR. On the other hand, virtually all neocortical regions receive significantly denser projections from the rostral than from the caudal DR. The present results demonstrate that dorsal raphe fibers project significantly throughout widespread regions of the midbrain and forebrain.

A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat.

The ability to determine the location of a sound source is fundamental to hearing. However, auditory space is not represented in any systematic manner on the basilar membrane of the cochlea, the sensory surface of the receptor organ for hearing. Understanding the means by which sensitivity to spatial cues is computed in central neurons can therefore contribute to our understanding of the basic nature of complex neural representations. We review recent evidence concerning the nature of the neural representation of auditory space in the mammalian brain and elaborate on recent advances in the understanding of mammalian subcortical processing of auditory spatial cues that challenge the "textbook" version of sound localization, in particular brain mechanisms contributing to binaural hearing.

Mechanisms of Sound Localization in Mammals

1. We studied the sensitivity of cells in the medial superior olive (MSO) of the anesthetized cat to variations in interaural phase differences (IPDs) of low-frequency tones and in interaural time differences (ITDs) of tones and broad-band noise signals. Our sample consisted of 39 cells histologically localized to the MSO. 2. All but one of the cells had characteristic frequencies less than 3 kHz, and 79% were sensitive to ITDs and IPDs. More than one-half (56%) of the cells responded to monaural stimulation of either ear, and both the binaural and monaural responses were highly phase locked. All of the cells that were sensitive to IPDs and monaurally driven by either ear responded in accord with that predicted by the coincidence model of Jeffress, as judged by comparisons of the phases at which the monaural and binaural responses occurred. The optimal IPDs were tightly clustered between 0.0 and 0.2 cycles. Most cells exhibited facilitation of the response at favorable ITDs and inhibition at unfavorable ITDs compared with the monaural responses. 3. Cells in the MSO exhibited characteristic delay, as judged by a linear relationship between the mean interaural phase and stimulating frequency. Characteristic phases were clustered near 0 indicating the most cells responded maximally when the two input tones were in phase. With the use of the binaural beat stimulus we found no differential selectivity for either the direction or speed of interaural phase changes. 4. The cells were also sensitive to ITDs of broad-band noise signals. The ITD curve in response to broad-band noise was similar to that predicted by the composite curve, which was calculated by linearly summating the tonal responses over the frequencies in the response area of the cell. Most (93%) of the peaks of the composite curves were between 0 and +400 microseconds, corresponding to locations in the contralateral sound field. Moreover, computer cross correlations of the monaural spike trains were similar to the ITD curve generated binaurally for both correlated and uncorrelated noise signals to the two ears. Thus our data suggest that the cells in the MSO behave much like cross-correlators. 5. By combining data from different animals and lcoating each cell on a standard MSO, we found evidence for a spatial map of ITDs across the anterior-posterior (A-P) axis of the MSO.(ABSTRACT TRUNCATED AT 400 WORDS)

Interaural time sensitivity in medial superior olive of cat

A comprehensive search for subcortical projections to the cat superior colliculus was conducted using the retrograde horseradish peroxidase (HRP) method. Over 40 different subcortical structures project to the superior colliculus. The more notable among these are grouped under the following categories.



Visual structures: ventral lateral geniculate nucleus, parabigeminal nucleus, pretectal area (nucleus of the optic tract, posterior pretectal nucleus, nuclei of the posterior commissure).



Auditory structures: inferior colliculus (external and pericentral nuclei), dorsomedial periolivary nucleus, nuclei of the trapezoid body, ventral nucleus of the lateral lemniscus.



Somatosensory structures: sensory trigeminal complex (all divisions, but mainly the γ division of nucleus oralis), dorsal column nuclei (mostly cuneate nucleus), and the lateral cervical nucleus.



Catecholamine nuclei: locus coeruleus, raphe dorsalis, and the parabrachial nuclei.



Cerebellum: medial, interposed, and lateral nuclei, and the perihypoglossal nuclei.



Reticular areas: zona incerta, substantia nigra, midbrain tegmentum, nucleus paragigantocellularis lateralis, and the hypothalamus.



Evidence is presented that only the parabigeminal nucleus, the nucleus of the optic tract, and the posterior pretectal nucleus project to the superficial collicular layers (striatum griseum superficiale and stratum opticum), while all other afferents terminate in the deeper layers of the colliculus. Also presented is information concerning the rostrocaudal distribution of some of these afferent connections. These findings stress the multiplicity and diversity of inputs to the deeper collicular layers, and more specifically, identify multiple sources of the physiologically well-known representations of the somatic and auditory modalities in the colliculus.

Sources of subcortical projections to the superior colliculus in the cat.

Previous studies suggest that the principal cells of the medial nucleus of the trapezoid body (MNTB) give rise to the projection from MNTB to the lateral superior olivary nucleus (LSO) of the same side, where they mediate rapid inhibitory effects of contralateral sound stimulation. In the present study, we explored certain morphological features of this connection as well as several other projections of the MNTB by using anterograde and retrograde axonal tracing methods. Following injections of tritiated leucine into MNTB, labeled axons reached LSO by passing ventral to, dorsal to, and through the medial superior olivary nucleus, and gave rise to labeling around the somata and proximal dendrites of LSO fusiform cells. As measured in autoradiograms of 2 micron plastic sections, these axons had a modal diameter of 5-6 micron. Terminal labeling, tentatively attributed to principal cell axons, was also seen in the ventral nucleus of the lateral lemniscus (VNLL) and the dorsomedial and ventromedial periolivary nuclei. HRP injections into the LSO and the VNLL showed that the principal cell projected to both of these nuclei and revealed a topographic arrangement of the projection to the LSO which is consistent with tonotopic maps determined electrophysiologically. Control HRP injections demonstrated that other minor projections of the MNTB arose from minor cell populations in this nucleus. The findings provide a morphological correlate of certain physiological findings and suggest a wider role for the MNTB in the ascending auditory system than previously has been supposed.

The projections of principal cells of the medial nucleus of the trapezoid body in the cat

This study examines the dorsal nucleus of the lateral lemniscus (DNLL) and its afferent and efferent connections. In Nissl-stained material, DNLL has three parts: dorsal, ventral, and lateral. Although each part contains neurons with similar Nissl patterns, the subdivisions may be distinguished by the size, shape, and orientation of the cells. The lateral DNLL contains a mixture of DNLL neurons and cells from the sagulum. Afferent connections to DNLL were investigated with anterograde axonal transport techniques. Bilateral inputs to DNLL arise from the anteroventral cochlear nucleus and lateral superior olive, while unilateral inputs are provided by the ipsilateral medial superior olive and the contralateral DNLL. The inputs appear to have a tonotopic organization. Afferent fibers to DNLL form horizontal bands that are continuous both mediolaterally and rostrocaudally. All parts of DNLL do not share the same inputs, and a medial-to-lateral gradient in the labeling of some pathways is evident. To study the efferent connections of DNLL, both retrograde and anterograde axonal transport techniques were used. The DNLL projects to the inferior colliculus and the contralateral DNLL. The topography of these projections suggests that areas of similar tonotopic organization are connected. In the inferior colliculus, the projection is heaviest to the central nucleus and extends to the adjacent dorsal and caudal cortex, the rostral pole nucleus, and the ventrolateral nucleus. Axons from DNLL terminate along the fibrodendritic laminae of the central nucleus as bands that are prominent on the contralateral side, whereas those on the ipsilateral colliculus are more diffuse. The afferent and efferent connections of DNLL constitute a multisynaptic pathway, parallel to the other ascending pathways to the inferior colliculus. The other ascending pathways include the direct pathways from the cochlear nucleus to the inferior colliculus and the indirect pathways via the superior olivary complex. Ascending pathways are discussed as to their relationship to the subdivisions of the inferior colliculus, the laterality of their projections, and their banding patterns in the central nucleus. In contrast to the excitatory pathways to the inferior colliculus, the neurons in DNLL may use GABA as a neurotransmitter. Axons from the DNLL terminate in the inferior colliculus as bands that could have a unique inhibitory function. Thus, the multisynaptic, DNLL pathway may provide feed-forward inhibitory inputs to the inferior colliculus, bilaterally, and to the contralateral DNLL.

Connections of the dorsal nucleus of the lateral lemniscus: an inhibitory parallel pathway in the ascending auditory system?

The dendritic and axonal morphology of neurons in the inferior colliculus of the cat was investigated after intracellular injection of HRP, in vivo. All injected axons gave off local collaterals, and most showed a widespread distribution and lacked a specific orientation. In contrast, the dendrites of injected neurons were distinguished by their degree of orientation and the direction of the longest axis of orientation. Dendrites showed a high, moderate, or low degree of orientation. Most highly oriented cells had their longest axis in the rostrocaudal direction with fewer in the mediolateral direction. In the central nucleus, only the rostrocaudally oriented cells correspond to the disc-shaped cells identified in Golgi preparations. Unlike most cells in our sample, the two cells that were disc-shaped had axons that were parallel to the orientation of the dendritic tree. In the dorsal cortex, rostrocaudally oriented cells also were found, but they had unoriented axons. In both the central nucleus and dorsal cortex, cells with a mediolateral axis of orientation or no specific orientation correspond to stellate cells and had axons with widespread local collaterals.



These results suggest that an extensive network of local axon collaterals may contribute to neural processing within the inferior colliculus. In the central nucleus, local axons may establish connections within or across the fibrodendritic laminae. In the dorsal cortex, the local and afferent axons may form a complex reticular network. Finally, some injected cells had axons terminating locally and also entering the brachium of the inferior colliculus. This suggests that cells in the inferior colliculus may function as both interneurons and projection neurons.

Dendritic and axonal morphology of HRP-injected neurons in the inferior colliculus of the cat.

It is known that the dorsal cochlear nucleus and medial geniculate body in the auditory system receive significant inputs from somatosensory and visual-motor sources, but the purpose of such inputs is not totally understood. Moreover, a direct connection of these structures has not been demonstrated, because it is generally accepted that the inferior colliculus is an obligatory relay for all ascending input. In the present study, we have used auditory neurophysiology, double labeling with anterograde tracers, and retrograde tracers to investigate the ascending projections of the cochlear nuclear complex. We demonstrate that the dorsal cochlear nucleus and the small cell cap of the ventral cochlear nucleus have a direct projection to the medial division of the medial geniculate body. These direct projections from the cochlear nucleus complex bypass the inferior colliculus and are widely distributed within the medial division of the medial geniculate, suggesting that the projection is not topographic. As a nonlemniscal auditory pathway that parallels the conventional auditory lemniscal pathway, its functions may be distinct from the perception of sound. Because this pathway links the parts of the auditory system with prominent nonauditory, multimodal inputs, it may form a neural network through which nonauditory sensory and visual-motor systems may modulate auditory information processing.

https://www.jneurosci.org/content/jneuro/22/24/10891.full.pdf

Craig K. Henkel

Papers

Sources of subcortical projections to the superior colliculus in the cat.

The projections of principal cells of the medial nucleus of the trapezoid body in the cat

Connections of the dorsal nucleus of the lateral lemniscus: an inhibitory parallel pathway in the ascending auditory system?

Dendritic and axonal morphology of HRP-injected neurons in the inferior colliculus of the cat.

Direct projections from cochlear nuclear complex to auditory thalamus in the rat.