Gender differences in cerebral metabolism for color processing in mice: A PET/MRI Study

Introduction Color processing is a central component of mammalian vision. Gender-related differences of color processing revealed by non-invasive functional transcranial Doppler ultrasound suggested right hemisphere pattern for blue/yellow chromatic opponency by men, and a left hemisphere pattern by women. Materials and Methods The present study measured the accumulation of [18F]fluorodeoxyglucose ([18F]FDG) in mouse brain using small animal positron emission tomography and magnetic resonance imaging (PET/MRI) with statistical parametric mapping (SPM) during light stimulation with blue and yellow filters compared to darkness condition. Results PET revealed a reverse pattern relative to dark condition compared to previous human studies: Male mice presented with left visual cortex dominance for blue through the right eye, while female mice presented with right visual cortex dominance for blue through the left eye. We applied statistical parametric mapping (SPM) to examine gender differences in activated architectonic areas within the orbital and medial prefrontal cortex and related cortical and sub-cortical areas that lead to the striatum, medial thalamus and other brain areas. The metabolic connectivity of the orbital and medial prefrontal cortex evoked by blue stimulation spread through a wide range of brain structures implicated in viscerosensory and visceromotor systems in the left intra-hemispheric regions in male, but in the right-to-left inter-hemispheric regions in female mice. Color functional ocular dominance plasticity was noted in the right eye in male mice but in the left eye in female mice. Conclusions This study of color processing in an animal model could be applied in the study of the role of gender differences in brain disease.


Gender-related Cortical Networks Activated by Blue Color
Blue color activated in male mice the left, but the right in female mice the area of the orbital and medial prefrontal cortex (OMPFC) with intra-and inter-hemispheric connections to the striatum, medial thalamus and other brain regions, respectively. Each network receives sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory and visual) that appear to be related to feeding. There are also many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum. The OMPFC is a complex region containing agranular, dysgranular, and granular regions interact with basal ganglia-thalamic circuit and limbic structures. These structures may also serve as substrate to integrate viscerosensory information with affective signals. The medial network comprise areas on the medial frontal surface together with a few select areas in the orbital cortex, which form the major output from the OMFPC to the hypothalamus and brain stem (especially the periaqueductal gray). The Blue color activation of the medial network as a visceromotor system provides frontal cortical influence over autonomic and endocrine function. The functions of the specific structures are hereby provided in Table 1, and illustrated in the attached Figure S1. crossed fiber tracts on each side of the brainstem; main central connection of the oculomotor nerve (III), trochlear nerve (IV) and abducens (VI) and integrates gaze centers (frontal eye field) and head movement (vestibulocochlear nerve II) [7]; involved in saccadic eye movement, vestibulo-ocular and optokinetic reflexes. CA1 field CA1 of hippocampus the hippocampal formation consists of six-layered periallocortical regions (the entorhinal cortex, parasubiculum, presubiculum and postsubiculum) and three-layered allocortical regions (the subiculum, Ammon's horn and dentate gyrus). In primates it is located in the medial temporal lobe, below the cortical surface; it contains two main interlocking parts: the hippocampus proper (also called Ammon's horn) and the dentate gyrus; CA1 performs a match-mismatch comparison of memory retrieval with sensory input [8]. CA2 field CA2 of hippocampus has several features that distinguish it from CA1 and CA3, including a unique gene expression profile, failure to display long-term potentiation and relative resistance to cell death [9]; involved in social memory -the ability of the animal to remember another animal of the same species (conspecific) [10]. CA3 field CA3 of hippocampus located in the medial temporal lobe, lesions of the CA3 and dentate gyrus strongly reduce the enhanced exploration associated with displaced objects, beyond the reduction caused by CA1 lesions [8]. Cg1 and Cg2 cingulate cortex area 1 and area 2 the cingulate cortex, a part of the limbic cortex situated in the medial aspect of the cerebral cortex. It receives inputs from the thalamus and the neocortex, and projects to the entorhinal cortex via the cingulum. It is involved with emotion formation and processing [11], learning and memory [12]. The cingulate cortex area 1 is the rostral part of the anterior cingulate cortex and the frontal area 2 is the caudal and dorsal parts of the anterior cingulate cortex. The anterior cingulate cortex is organized topographically; stimulus attributes predicting reward or no reward are represented in the rostral (Cg1) and ventral (Cg3) parts of the anterior cingulate cortex, while Cg2 (the caudal and dorsal parts) of the anterior cingulate cortex are related to execution of learned instrumental behaviours [13]. CIC central nucleus of the inferior colliculus is the major subcortical auditory integration center receiving extrinsic ascending inputs from almost all auditory brainstem nuclei as well as descending inputs from the thalamus and cortex, and intrinsic intracollicular connections for inhibition after hearing onset [14]. Many units in the central nucleus of the inferior colliculus (CIC) respond to amplitude and frequency modulated tones, features found in communication signals [15]. CM central medial thalamic nucleus central medial nucleus (CM) is a prominent cell group of the rostral intralaminar nucleus (ILN) of the thalamus. The primary projections of the CM are the anterior and posterior regions of cortex, the claustrum, the caudateputamen, the nucleus accumbens (ACC), the olfactory tubercle, and the amygdala. The rostral CM (CMr) more strongly targets limbic structures that include medial agranular, anterior cingulate, prelimbic, dorsolateral orbital and dorsal agranular insular cortices, the dorsal striatum, the ACC, and the basolateral nucleus of the amygdala. While the caudal CM (CMc) more heavily projects to sensorimotor cortical structures that include the ventrolateral, lateral and dorsolateral orbital cortices, dorsal, ventral and posterior agranular insular cortices, visceral cortex, primary somatosensory and motor cortices, and perirhinal cortex. The main CMc subcortical projections are to the dorsal striatum and the lateral, central, anterior cortical, and basomedial nuclei of amygdala. The function of CM may be to integrate affective, cognitive and sensorimotor functions for goaldirected behaviour [16]. Cpu caudate putamen parts of the basal ganglia which are broadly responsible for sensorimotor coordination, for planned (cognition; caudate) and implemented (sensorimotor coordination; putamen) actions [17]. DG dendate gyrus the dentate gyrus is the input region of the hippocampus. The cell body of the dentate pyramidal basket cell is located just within the granule cell layer at its border with the polymorphic layer (PoDG). The granule cell layer encloses a cellular region, the PoDG constitutes the third layer of the dentate gyrus. The most prominent cell types located in the PoDG is the mossy cell. The dentate gyrus acts as a preprocessor of incoming information, preparing it for subsequent processing in CA3 [18]. The dentate gyrus receives its major input from the entorhinal cortex, via the so-called perforant pathway. The glutamatergic supramammillary neurons that project to the dentate gyrus also colocalize calretinin; some of these cells also colocalize substance P. The noradrenergic fibers terminate mainly in the polymorphic layer of the dentate gyrus and extend into the stratum lucidum of CA3. A major portion of the fibers of the septal projection from the forebrain to the dentate gyrus are cholinergic. Many of the other septal cells that project to the dentate gyrus are GABAergic [19]. DMTg dorsomedial tegmental area the pontine dorsomedial tegmentum appears to participate in regulating the neural mechanism for lordosis [20]. DP dorsal peduncular cortex refers to a cytoarchitectonic area on the medial surface of the cerebral hemisphere rostral to the septum, ventral to the infralimbic area and dorsal to the tenia tecta in the mouse [21]. The mid-DP connect to rostrodorsomedial part of laminae I/II of Vc (rdm-I/II-Vc), periaqueductal gray and solitary tract nucleus, and ipsilaterally in the parabrachial nucleus, trigeminal mesencephalic nucleus, caudal most level of the granular and dysgranular insular cortex (GI/DI). The mid-DP neurons may regulate intraoral and perioral sensory processing (including nociceptive processing) [22]. DTT and VTT dorsal tenia tecta and ventral tenia tecta the dorsal (DTT) and ventral tenia tecta (VTT) are the two parts of the tenia tecta that contains four sublayers. High levels of OX 1 R mRNA have been detected in tenia tecta.
Orexin may have a role in regulation of feeding [23]. They receive direct input from the olfactory tract mitral cells as secondary olfactory structures involved in the discrimination and learning of odor stimuli, and in the production of appropriate behavioral responses [24]. ECIC external cortex of the inferior colliculus the inferior colliculus (IC) is a part of midbrain for processing center for monaural and binaural auditory signals [15]. It is sub-divided into the external cortex, lateral cortex, and central cortex. The IC performs the function of integrating multiple audio signals that help to filter out sounds from vocalizing, breathing, and chewing activities. GI granular insular cortex GI is situated just ventral to the secondary somatosensory cortex with a clear granular layer [2]. The integrity of the granular insula is necessary for exhibiting motivation to take nicotine and to relapse to nicotine seeking but not for consuming food pellets or to relapse for food seeking [25]. GrO granule cell layer of the olfactory bulb Gro is the deepest layer in the olfactory bulb, made up of dendrodendritic granule cells that synapse to the mitral cell layer. GrO receives excitatory glutamate signals from the basal dendrites of the mitral and tufted cells, and in turn releases GABA to cause an inhibitory effect on the mitral cell. Propagated spikes in granule cells also mediate lateral inhibition to other mitral/tufted cells [26]. Gus gustatory thalamic nucleus gustatory thalamus is the functional name for the parvicellular region of the ventroposteromedial (VPMpc) nucleus of the thalamus. The VPMpc critical for the preparatory (i.e. food-seeking) rather than the consummatory (i.e. food-eating) aspects of taste-guided behaviour [27]. HCNP hippocampal cholinergic neurostimulatin g peptide act cooperatively with nerve growth factor (NGF), to regulate cholinergic phenotype development in the medial septal nucleus [28]. HCNP and its precursor can be a candidate for the key molecules elucidating the underlying association among A-beta, phosphorylated tau, degeneration of dendritic spine and decrease of acetylcholine in Alzheimer brain [29]. IL infralimbic cortex located in the ventromedial prefrontal cortex which is important in tonic inhibition of subcortical structures and emotional responses, such as fear. IL regulates the acquisition and expression of behavioral flexibility. IL extensively innervates amygdala nuclei, hypothalamus, most notably including the dorsomedial and lateral hypothalamus [30][31][32]. InC interstitial nucleus of Cajal interstitial nucleus of Cajal (InC) in the midbrain reticular formation regulates the ability to hold eccentric vertical eye position after saccades, phase advance and decreased gain of the vestibule ocular reflex (VOR) induced by sinusoidal vertical rotation. Furthermore, the InC region of alert animals contains many burst-tonic and tonic neurons whose activity is closely correlated with vertical eye movement, not only during spontaneous saccades, but also during VOR, smooth pursuit and optokinetic eye movement [33]. is part of the basal ganglia together with the caudate and putamen. The globus pallidus, is immediately medial to the putamen and has a medial (internal -Gpi) and lateral (external -Gpe) segment. The Gpe is centrally located within the multiple feedback loops of basal ganglia circuits [35]. The output of Gpe is GABAergic, and inhibitory on its targets [36], inputs to Gpe/Gpi can arrive from cerebral cortex via two major distinct pathways, one passing through the striatum (Str) and the other through the subthalamic nucleus (STN). Other inputs to Gpe/Gpi originate from the intralaminar thalamic nuclei and brainstem nuclei including the pedunculopontine tegmentum [37]. The Gpe receives a strong glutamatergic projection from the subthalamic nucleus, and both form a coupled pacemaker, which is used as target for deep brain stimulation in Parkinson's disease [38]. LO lateral orbital frontal cortex the lateral orbital frontal cortex (OFC) has three sectors: caudal sector has strong connections with the amygdala, midline thalamus, non-isocortical insula and temporal pole; anterior sector has more pronounced connections with the granular insula, association cortex, mediodorsal thalamus, inferior parietal lobule and dorsolateral prefrontal cortex (PFC), involved in higher-order cognition [39]. The lateral OFC is involved in stimulus-outcome associations and the evaluation and possibly reversal of behaviour [40]. LSI lateral septal nucleus lateral septal nucleus is divided into major rostral, caudal, and ventral parts. LSN participates in neuroendocrine regulation of the sexual system. It is a chronoregulatory structure which is responsible for the biorhythmologic organization of the functions of the mammalian organism [41].
M2 secondary motor cortex the secondary motor cortex (M2) is involved in planning of movement. M2 projections target medial/intralaminar thalamic nuclei, which are known to interact with prefrontal areas associated with working memory, perception, and sensory-guided movements. Both layer 5 of the primary and secondary motor cortices projections have many common targets including the basal ganglia, midbrain and medulla. The motor functional roles of M2 may be mainly mediated through layer 6 M2 projections that communicate with frontal areas [42]. MO medial orbital frontal cortex medial orbital (MO) and ventral orbital (VO) cortices are prominent divisions of the orbitomedial prefrontal cortex. Distributes the main cortical targets of MO were the orbital, ventral medial prefrontal (mPFC), agranular insular, piriform, retrosplenial, and parahippocampal cortices. The main subcortical targets of MO were the medial striatum, olfactory tubercle, claustrum, nucleus accumbens, septum, substantia innominata, lateral preoptic area, and diagonal band nuclei of the basal forebrain; central, medial, cortical, and basal nuclei of amygdala; paratenial, mediodorsal, and reuniens nuclei of the thalamus; posterior, supramammillary, and lateral nuclei of the hypothalamus; and periaqueductal gray, ventral tegmental area, substantia nigra, dorsal and median raphe, laterodorsal tegmental, and incertus nuclei of the brainstem [43,44]. The medial OFC is involved in making stimulus-reward associations and with the reinforcement of behavior [40].
MS medial septal nucleus the hippocampus receives cholinergic projections from the medial septal nucleus (MS) and Broca's diagonal band that terminate in the CA1, CA3, and dentate gyrus regions [29]. The hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in the MS [29]. HCNP may be implicated in the underlying association among A-beta, phosphorylated tau, degeneration of dendritic spine and decrease of acetylcholine in Alzheimer brain [29]. PAG (dmPAG) dorsomedial periaqueductal gray located in the midbrain, its major functions include analgesia, fear and anxiety, vocalization, lordosis and cardiovascular control [43]. It receives nociceptive afferent neurons from the spinal cord and sends nociceptive projections to thalamic nuclei. It interacts with the amygdala and its lesion alters fear and anxiety produced by stimulation of amygdala. When stimulated it produces vocalization and its lesion produces mutism [44]. The PAG brainstem structures are rich in 5-hydroxytryptamine (5-HT) inputs related to the modulation of pain. The 5-HT2A and 5-HT2C serotonergic receptors in dmPAG and vlPAG columns, plays a critical role in the elaboration of post-ictal antinociception [44]. PaS parasubiculum Pas is major input structure of layer 2 of medial entorhinal cortex, where most grid cells are found. It is a prime target of GABAergic and cholinergic medial septal inputs. It receives input from structures that include the subiculum, presubiculum, and anterior thalamus. The PaS might shape entorhinal theta rhythmicity and the (dorsoventral) integration of information across grid scales [45]. PL prelimbic cortical area the infralimbic and prelimbic cortices and the lateral prefrontal cortex (i.e. agranular insular cortices), have reciprocal connections with the perirhinal and entorhinal cortex, and with the CA1 and subiculum of the hippocampal formation. PL region is involved in attentional and response selection functions as well as visual working memory [46].
Po posterior thalamic nuclear group consisting of the centre médian and parafascicular nuclei, involved in limbic motor functions [47].
PoDG polymorphic cell layer of the dentate gyrus the granule cell layer encloses a cellular region, the polymorphic cell layer, which constitutes the third layer of the dentate gyrus. A number of cell types are located in the polymorphic layer but the most prominent is the mossy cell. Majority of mossy fiber collaterals in the polymorphic cell layer terminate on GABAergic interneurons. Besides the mossy cell, there are a number of fusiform cells in the polymorphic layer. The main difference between the fusiform cell types is whether they have spines or not and the characteristic shapes and sizes of the spines. One type the HIPP cell (hilar perforant path-associated cell) are somatostatin-positive cells which colocalize with GABA, and are the source of the somatostatin immunoreactive fibers and terminals in the outer two-thirds of the molecular layer [48]. PrS presubiculum presubiculum and parasubiculum are richly interconnected with excitatory synapses. These interconnections can generate giant excitatory synaptic potentials that support the bursting behaviour exhibited by these neurons. Any of the excitatory inputs to deep layer cells can trigger the population bursts and specific inputs from entorhinal cortex produce the after-discharges [49]. R red nucleus the red nucleus caudal part is a structure in the midbrain, while the rostral part is of the diencephalon [50]. The occulomotor nerves traverses only in the midbrain part of the red nucleus. The red nucleus sends its axons to the olive (rubro-olivary and reticulo-olivary fibres) and spinal cord (rubrospinal tract). It is pale pink in color; the color is believed to be due to iron, which is present in the red nucleus in at least two different forms: hemoglobin and ferritin. Its functions includes the coordination of muscle tone, body position and gait [50]. RI rostral interstitial nucleus of medial longitudinal fasciculus the rostral interstitial nucleus of medial longitudinal fasciculus (RIMLF) is a portion of the medial longitudinal fasciculus which controls vertical gaze. They project to the vestibular nuclei [51].
S2 secondary somatosensory cortex activated in response to light touch, pain, visceral sensation, and tactile attention [52] SPFPC subparafascicul ar thalamic nucleus parvocellular part parvocellular subparafascicular thalamic nucleus (SPFPC) is located in the posterior thalamus. The medial SPFPC may process inputs important for sexual behavior, whereas the lateral SPFp may be involved in convergence of auditory and nociceptive inputs important for conditioned fear responses [53]. VL ventrolateral thalamic nucleus lesions of the ventrolateral thalamic nucleus strongly hindered the switching of motor activity under the control of the corticospinal tract in rats subjected to section of the rubrospinal tract and lesioning of the red nucleus [54]. There is a role for the VL in sensory processing of synesthesia in which auditory stimuli produced tactile percepts. This suggests that reorganization of thalamocortical axonal connectivity can lead to major changes in perception [55]. VO ventral orbital prefrontal cortex medial orbital (MO) and ventral orbital (VO) cortices are prominent divisions of the orbitomedial prefrontal cortex. Distributes to some of these same sites, notably to the striatum, but lacks projections to parts of limbic cortex, to nucleus accumbens, and to the amygdala. VO distributes much more strongly, however, than MO to the medial (frontal) agranular, anterior cingulate, sensorimotor, posterior parietal, lateral agranular retrosplenial, and temporal association cortices. VO performs functions such as directed attention [56]. VPL ventral posterolateral thalamic nucleus VPL is more important for transmitting visceral nociceptive signals from Brodmann areas 3, 1 and 2 or primary sensorimotor cortex [57].
VPM ventral posteromedial thalamic nucleus VPM conveys facial sensory information of the trigeminothalamic tract, from the solitary tract and the trigeminal nerve and projects to the postcentral gyrus. Primary taste afferent inputs is received from the solitary tract and projects to the cortical gustatory area [58]. Hippocampal-Prefrontal Cortex Projections 13a, 13b, 14r, 14c, and llm areas within the hippocampus, the principal projection to the OMPFC arises in the subiculum and terminates in the medial orbital areas 13a, 13b, 14r, 14c, and llm. The caudal areas 13a, 13b, and 14c receive the heaviest projection [59].