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1.
Commun Biol ; 7(1): 212, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38378797

ABSTRACT

Children's secure attachment with their primary caregivers is crucial for physical, cognitive, and emotional maturation. Yet, the causal links between specific parenting behaviors and infant attachment patterns are not fully understood. Here we report infant attachment in New World monkeys common marmosets, characterized by shared infant care among parents and older siblings and complex vocal communications. By integrating natural variations in parenting styles and subsecond-scale microanalyses of dyadic vocal and physical interactions, we demonstrate that marmoset infants signal their needs through context-dependent call use and selective approaches toward familiar caregivers. The infant attachment behaviors are tuned to each caregiver's parenting style; infants use negative calls when carried by rejecting caregivers and selectively avoid neglectful and rejecting caregivers. Family-deprived infants fail to develop such adaptive uses of attachment behaviors. With these similarities with humans, marmosets offer a promising model for investigating the biological mechanisms of attachment security.


Subject(s)
Callithrix , Parenting , Child , Infant , Animals , Humans , Parenting/psychology , Caregivers/psychology , Anxiety , Parents/psychology
2.
Commun Biol ; 6(1): 1231, 2023 12 05.
Article in English | MEDLINE | ID: mdl-38052969

ABSTRACT

Calcitonin receptor (Calcr) and its brain ligand amylin in the medial preoptic area (MPOA) are found to be critically involved in infant care and social contact behaviors in mice. In primates, however, the evidence is limited to an excitotoxic lesion study of the Calcr-expressing MPOA subregion (cMPOA) in a family-living primate species, the common marmoset. The present study utilized pharmacological manipulations of the cMPOA and shows that reversible inactivation of the cMPOA abolishes infant-care behaviors in sibling marmosets without affecting other social or non-social behaviors. Amylin-expressing neurons in the marmoset MPOA are distributed in the vicinity of oxytocin neurons in the anterior paraventricular nucleus of the hypothalamus. While amylin infusion facilitates infant carrying selectively, an oxytocin's inverse agonist, atosiban, reduces physical contact with non-infant family members without grossly affecting infant care. These data suggest that the amylin and oxytocin signaling mediate intrafamilial social interactions in a complementary manner in marmosets.


Subject(s)
Oxytocin , Preoptic Area , Humans , Mice , Animals , Oxytocin/pharmacology , Callithrix , Islet Amyloid Polypeptide , Drug Inverse Agonism , Social Behavior
3.
Commun Biol ; 5(1): 1243, 2022 11 21.
Article in English | MEDLINE | ID: mdl-36411342

ABSTRACT

Like humans, common marmoset monkeys utilize family cooperation for infant care, but the neural mechanisms underlying primate parental behaviors remain largely unknown. We investigated infant care behaviors of captive marmosets in family settings and caregiver-infant dyadic situations. Marmoset caregivers exhibited individual variations in parenting styles, comprised of sensitivity and tolerance toward infants, consistently across infants, social contexts and multiple births. Seeking the neural basis of these parenting styles, we demonstrated that the calcitonin receptor-expressing neurons in the marmoset medial preoptic area (MPOA) were transcriptionally activated during infant care, as in laboratory mice. Further, site-specific neurotoxic lesions of this MPOA subregion, termed the cMPOA, significantly reduced alloparental tolerance and total infant carrying, while sparing general health and other social or nonsocial behaviors. These results suggest that the molecularly-defined neural site cMPOA is responsible for mammalian parenting, thus provide an invaluable model to study the neural basis of parenting styles in primates.


Subject(s)
Callithrix , Preoptic Area , Humans , Mice , Animals , Receptors, Calcitonin/genetics , Neurons , Mammals
4.
Curr Biol ; 32(20): 4521-4529.e4, 2022 10 24.
Article in English | MEDLINE | ID: mdl-36103877

ABSTRACT

Approximately 20%-30% of infants cry excessively and exhibit sleep difficulties for no apparent reason, causing parental stress and even triggering impulsive child maltreatment in a small number of cases.1-8 While several sleep training methods or parental education programs may provide long-term improvement of infant cry and sleep problems, there is yet to be a conclusive recommendation for on-site behavioral interventions.9-13 Previously we have reported that brief carrying of infants transiently reduces infant cry via the transport response, a coordinated set of vagal activation and behavioral calming conserved in altricial mammals.14-18 In this study, we disentangled complex infant responses to maternal holding and transport by combining subsecond-scale, event-locked physiological analyses with dynamic mother-infant interactions. Infant cry was attenuated either by maternal carrying or by reciprocal motion provided by a moving cot, but not by maternal holding. Five-minute carrying promoted sleep for crying infants even in the daytime when these infants were usually awake, but not for non-crying infants. Maternal laydown of sleeping infants into a cot exerted bimodal effects, either interrupting or deepening the infants' sleep. During laydown, sleeping infants were alerted most consistently by the initiation of maternal detachment, then calmed after the completion of maternal detachment in a successful laydown. Finally, the sleep outcome after laydown was associated with the sleep duration before the laydown onset. These data propose a "5-min carrying, 5- to 8- min sitting" scheme for attending to infant cry and sleep difficulties, which should be further substantiated in future studies. VIDEO ABSTRACT.


Subject(s)
Mother-Child Relations , Sleep Wake Disorders , Infant , Animals , Child , Humans , Sleep/physiology , Anxiety , Research Design , Mammals
5.
Anim Cogn ; 25(1): 33-41, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34156548

ABSTRACT

Phobia against spiders or snakes is common in humans, and similar phobia-like behaviors have been observed in non-human animals. Visual images of snakes elicit phobia in humans, but sensory modalities that cause snake aversion in non-human animals are not well examined. In this study, we examined visually induced snake aversion in two rodent species. Using a three-compartment experimental chamber, reactions to images of snakes were compared between the diurnal precocious rodent Octodon degus and nocturnal laboratory mice. The snakes whose images were presented do not live in the original habitats of degus or mice. Snake aversion was assessed by presenting snake vs. no-image, snake vs. flower, snake vs. degu, and snake vs. mouse images. The time spent in a compartment with the snake image and with the non-snake images were measured. Degus avoided images of snakes in every tests. In contrast, mice did not display snake aversion. Degus are diurnal animals, i.e., visual information is important for their survival. Since mice are nocturnal, visual information is less important for survival. Such behavioral differences in the two species may explain the difference in visually induced aversion to snakes. A principal component analysis of the stimulus images suggests that elementary cues, such as color, do not explain the differences in the species' aversion to snakes. Finally, snake aversion in degus suggests that aversion is innate, since the animals were born and raised in a laboratory.


Subject(s)
Avoidance Learning , Octodon , Animals , Circadian Rhythm , Mice , Mice, Inbred C57BL , Snakes
6.
Anim Cogn ; 25(2): 297-306, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34417921

ABSTRACT

Social animals likely recognize emotional expressions in other animals. Recent studies suggest that mice can visually perceive emotional expressions of other mice. In the first experiment, we measured the preference of mice for two different facial expressions (a normal facial expression and an expression of negative emotion such as pain) of rats, mice, and humans. Results revealed that mice showed a slight preference for the normal expression over the face expressing pain in the case of rats, but no preference in the case of others. In the second experiment, we trained mice to discriminate between the two facial expressions in an operant chamber with a touch screen. They could discriminate facial expressions of mice and rats, but they did not show discrimination of human facial expressions. Principal component analysis of the images of stimuli reveals negative correlation between pixel-based dissimilarity of training stimuli and the number of sessions to criterion. The mice showed generalization to novel images of the mouse faces with and without pain but did not maintain their discriminative behavior when new rat faces were shown. These results suggest that mice display category discrimination of conspecific facial expressions but not of other species.


Subject(s)
Discrimination, Psychological , Facial Expression , Animals , Emotions , Mice
7.
Cell Rep ; 35(9): 109204, 2021 06 01.
Article in English | MEDLINE | ID: mdl-34077719

ABSTRACT

Maternal mammals exhibit heightened motivation to care for offspring, but the underlying neuromolecular mechanisms have yet to be clarified. Here, we report that the calcitonin receptor (Calcr) and its ligand amylin are expressed in distinct neuronal populations in the medial preoptic area (MPOA) and are upregulated in mothers. Calcr+ MPOA neurons activated by parental care project to somatomotor and monoaminergic brainstem nuclei. Retrograde monosynaptic tracing reveals that significant modification of afferents to Calcr+ neurons occurs in mothers. Knockdown of either Calcr or amylin gene expression hampers risk-taking maternal care, and specific silencing of Calcr+ MPOA neurons inhibits nurturing behaviors, while pharmacogenetic activation prevents infanticide in virgin males. These data indicate that Calcr+ MPOA neurons are required for both maternal and allomaternal nurturing behaviors and that upregulation of amylin-Calcr signaling in the MPOA at least partially mediates risk-taking maternal care, possibly via modified connectomics of Calcr+ neurons postpartum.


Subject(s)
Behavior, Animal/physiology , Maternal Behavior/physiology , Preoptic Area/metabolism , Receptors, Calcitonin/metabolism , Risk-Taking , Signal Transduction , Animals , Estrogens/metabolism , Female , Gene Silencing , Gene Targeting , Islet Amyloid Polypeptide/metabolism , Lactation , Ligands , Male , Mice, Inbred C57BL , Neurons/metabolism , Postpartum Period , Prolactin/metabolism , Synapses/metabolism , Up-Regulation
8.
Psychiatry Clin Neurosci ; 74(10): 516-526, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32592505

ABSTRACT

Behaviors comparable to human child maltreatment are observed widely among mammals, in which parental care is mandatory for offspring survival. This article first reviews the recent findings on the neurobiological mechanisms for nurturing (infant caregiving) behaviors in mammals. Then the major causes of attack/desertion toward infants (conspecific young) in nonhuman mammals are classified into five categories. Three of the categories are 'adaptive' in terms of reproductive fitness: (i) attack/desertion toward non-offspring; (ii) attack/desertion toward biological offspring with low reproductive value; and (iii) attack/desertion toward biological offspring under unfavorable environments. The other two are nonadaptive failures of nurturing motivation, induced by: (iv) caregivers' inexperience; or (v) dysfunction in caregivers' brain mechanisms required for nurturing behavior. The proposed framework covering both adaptive and nonadaptive factors comprehensively classifies the varieties of mammalian infant maltreatment cases and will support the future development of tailored preventive measures for each human case. Also included are remarks that are relevant to interpretation of available animal data to humans: (1) any kind of child abuse/neglect is not justified in modern human societies, even if it is widely observed and regarded as adaptive in nonhuman animals from the viewpoint of evolutionary biology; (2) group-level characteristics cannot be generalized to individuals; and (3) risk factors are neither deterministic nor irreversible.


Subject(s)
Adaptation, Physiological/physiology , Behavior, Animal/physiology , Biological Evolution , Child Abuse , Maternal Behavior/physiology , Motivation/physiology , Paternal Behavior/physiology , Preoptic Area/physiology , Animals , Child , Humans
9.
J Cereb Blood Flow Metab ; 40(6): 1182-1192, 2020 06.
Article in English | MEDLINE | ID: mdl-31366299

ABSTRACT

Rodents display "empathy" defined as perceived physical pain or psychological stress by cagemates when co-experiencing socially distinct traumatic events. The present study tested the hypothesis that empathy occurs in adult rats subjected to an experimental neurological disorder, by allowing co-experience of stroke with cagemates. Psychological stress was measured by general locomotor activity, Rat Grimace Scale (RGS), and plasma corticosterone. Physiological correlates were measured by Western blot analysis of advanced glycation endproducts (AGE)-related proteins in the thymus. General locomotor activity was impaired in stroke animals and in non-stroke rats housed with stroke rats suggesting transfer of behavioral manifestation of psychological stress from an injured animal to a non-injured animal leading to social inhibition. RGS was higher in stroke rats regardless of social settings. Plasma corticosterone levels at day 3 after stroke were significantly higher in stroke animals housed with stroke rats, but not with non-stroke rats, indicating that empathy upregulated physiological stress level. The expression of five proteins related to AGE in the thymus reflected the observed pattern of general locomotor activity, RGS, and plasma corticosterone levels. These results indicate that stroke-induced psychological stress manifested on both the behavioral and physiological levels and appeared to be affected by empathy-associated social settings.


Subject(s)
Empathy , Infarction, Middle Cerebral Artery/psychology , Rats/psychology , Social Environment , Animals , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/physiopathology , Male , Rats, Sprague-Dawley , Receptor for Advanced Glycation End Products/metabolism , Stress, Psychological/etiology , Stress, Psychological/metabolism , Thymus Gland/metabolism
10.
Anim Cogn ; 23(1): 233-236, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31650291

ABSTRACT

Japanese eels (Anguilla japonica) were trained on a Morris-type spatial learning task. There were four tubes in a pool, but the eels could hide in only one of these. The eels learned the position of the open tube, and maintained their performance when the pool was rotated to remove possible intra-maze cues. The eels could not maintain their performance in a dark room, suggesting that spatial learning involved extra-maze visual cues. When the position of the open tube was randomly changed every day, the performance of the eels in finding the open tube did not improve.


Subject(s)
Anguilla , Animals , Cues , Japan , Spatial Learning
11.
Sci Rep ; 9(1): 13265, 2019 Sep 10.
Article in English | MEDLINE | ID: mdl-31501483

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Sci Rep ; 9(1): 5394, 2019 04 04.
Article in English | MEDLINE | ID: mdl-30948740

ABSTRACT

Two of the most common nonhuman animals that interact with humans are domestic dogs (Canis familiaris) and cats (Felis catus). In contrast to dogs, the ability of domestic cats to communicate with humans has not been explored thoroughly. We used a habituation-dishabituation method to investigate whether domestic cats could discriminate human utterances, which consisted of cats' own names, general nouns, and other cohabiting cats' names. Cats from ordinary households and from a 'cat café' participated in the experiments. Among cats from ordinary households, cats habituated to the serial presentation of four different general nouns or four names of cohabiting cats showed a significant rebound in response to the subsequent presentation of their own names; these cats discriminated their own names from general nouns even when unfamiliar persons uttered them. These results indicate that cats are able to discriminate their own names from other words. There was no difference in discrimination of their own names from general nouns between cats from the cat café and household cats, but café cats did not discriminate their own names from other cohabiting cats' names. We conclude that cats can discriminate the content of human utterances based on phonemic differences.


Subject(s)
Names , Animals , Auditory Perception , Cats , Dogs , Female , Humans , Male
13.
Clin Neurol Neurosurg ; 142: 145-147, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26866777

ABSTRACT

A close pathological link between stroke brain and heart failure may exist. Here, we discuss relevant laboratory and clinical reports demonstrating neural and cardiac myocyte cell death following ischemic stroke. Although various overlapping risk factors exist between cerebrovascular incidents and cardiac incidents, stroke therapy has largely neglected the cardiac pathological consequences. Recent preclinical stroke studies have implicated an indirect cell death pathway, involving toxic molecules, that originates from the stroke brain and produces cardiac cell death. In concert, previous laboratory reports have revealed a reverse cell death cascade, in that cardiac arrest leads to ischemic cell death in the brain. A deeper understanding of the crosstalk of cell death pathways between stroke and cardiac failure will facilitate the development of novel treatments designed to arrest the global pathology of both diseases thereby improving the clinical outcomes of patients diagnosed with stroke and heart failure.


Subject(s)
Brain Ischemia/complications , Heart/physiopathology , Stroke/complications , Cell Death/physiology , Heart Failure/etiology , Humans , Risk Factors
14.
Anim Cogn ; 19(3): 523-31, 2016 May.
Article in English | MEDLINE | ID: mdl-26801496

ABSTRACT

We showed mice videos of three conspecific social behaviors, namely sniffing, copulation, and fighting, in pairwise combinations using iPods and evaluated preference as determined by time spent in front of each iPod. Mice preferred the copulation video to the sniffing video, the fighting video to the sniffing video, and the fighting video to the copulation video. In Experiment 1a, we used a single video clip for each social behavior but used multiple video clips for each social behavior in Experiment 2a. Next, we trained mice to discriminate between the fighting and copulation videos using a conditioned-place-preference-like task in which one video was associated with injection of morphine and the other was not. For half of the subjects, the fighting video was associated with morphine injection, and for the other half, the copulation video was associated with morphine injection. After conditioning, the mice stayed longer in the compartment with the morphine-associated video. When tested with still images obtained from the videos, mice stayed longer in the compartment with still images from the video associated with morphine injection (Experiment 1b). When we trained mice with multiple exemplars, the subjects showed generalization of preference for new video clips never shown during conditioning (Experiment 2b). These results demonstrate that mice had a preference among videos of particular behavior patterns and that they could discriminate these videos as visual category. Although relationship between real social behaviors and their videos is still open question, the preference tests suggest that the mice perceived the videos as meaningful stimuli.


Subject(s)
Behavior, Animal/drug effects , Discrimination, Psychological/drug effects , Morphine/pharmacology , Social Behavior , Aggression , Animals , Conditioning, Operant/drug effects , Copulation , Mice , Mice, Inbred C57BL , Narcotics/pharmacology , Video Recording
15.
EMBO J ; 34(21): 2652-70, 2015 Nov 03.
Article in English | MEDLINE | ID: mdl-26423604

ABSTRACT

Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c-Fos expression pattern in the four nuclei of the preoptic-bed nuclei of stria terminalis (BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter-male aggression, solitary control). Specifically, neuronal activation in the central part of the medial preoptic area (cMPOA) and rhomboid nucleus of the BST (BSTrh) retroactively detected paternal and infanticidal motivation with more than 95% accuracy. Moreover, cMPOA lesions switched behavior in fathers from paternal to infanticidal, while BSTrh lesions inhibited infanticide in virgin males. The projections from cMPOA to BSTrh were largely GABAergic. Optogenetic or pharmacogenetic activation of cMPOA attenuated infanticide in virgin males. Taken together, this study identifies the preoptic-BST nuclei underlying social motivations in male mice and reveals unexpected complexity in the circuit connecting these nuclei.


Subject(s)
Paternal Behavior , Preoptic Area/physiology , Animals , Behavior, Animal , Brain Mapping , GABAergic Neurons/metabolism , Male , Mice , Preoptic Area/cytology , Proto-Oncogene Proteins c-fos/metabolism
16.
Front Syst Neurosci ; 8: 116, 2014.
Article in English | MEDLINE | ID: mdl-25009475

ABSTRACT

Modified mesenchymal stromal cells (MSCs) display a unique mechanism of action during the repair phase of traumatic brain injury by exhibiting the ability to build a biobridge between the neurogenic niche and the site of injury. Immunohistochemistry and laser capture assay have visualized this biobridge in the area between the neurogenic subventricular zone and the injured cortex. This biobridge expresses high levels of extracellular matrix metalloproteinases (MMPs), which are initially co-localized with a stream of transplanted MSCs, but later this region contains only few to non-detectable grafts and becomes overgrown by newly recruited host cells. We have reported that long-distance migration of host cells from the neurogenic niche to the injured brain site can be attained via these transplanted stem cell-paved biobridges, which serve as a key regenerative process for the initiation of endogenous repair mechanisms. Thus, far the two major schools of discipline in stem cell repair mechanisms support the idea of "cell replacement" and the bystander effects of "trophic factor secretion." Our novel observation of stem cell-paved biobridges as pathways for directed migration of host cells from neurogenic niche toward the injured brain site adds another mode of action underlying stem cell therapy. More in-depth investigations on graft-host interaction will likely aid translational research focused on advancing this stem cell-paved biobridge from its current place, as an equally potent repair mechanism as cell replacement and trophic factor secretion, into a new treatment strategy for traumatic brain injury and other neurological disorders.

17.
PLoS One ; 9(3): e90953, 2014.
Article in English | MEDLINE | ID: mdl-24621603

ABSTRACT

Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI.


Subject(s)
Brain Injuries/pathology , Brain Injuries/physiopathology , Cell- and Tissue-Based Therapy , Fetal Blood/cytology , Granulocyte Colony-Stimulating Factor/pharmacology , Motor Activity/drug effects , Animals , Behavior, Animal/drug effects , Brain Injuries/drug therapy , Brain Injuries/therapy , Cell Count , Combined Modality Therapy , Disease Models, Animal , Granulocyte Colony-Stimulating Factor/therapeutic use , Hippocampus/drug effects , Hippocampus/pathology , Humans , Male , Neurogenesis/drug effects , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects
18.
Brain Res ; 1559: 65-71, 2014 Apr 22.
Article in English | MEDLINE | ID: mdl-24602693

ABSTRACT

The timing of therapeutic intervention in traumatic brain injury (TBI) is critical. Although immediate cell death cascades have become established in adult TBI, the pathophysiology underlying neonatal TBI is poorly understood. The objective of the present study was to determine the role of cytokine regulation following TBI in neonatal rats. Seven-day-old Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Age-matched littermates that did not receive TBI served as the controls. Immediately following TBI, rats were euthanized, and the brains were divided into the ipsilateral and contralateral hemispheres then flash frozen. A BioRad 23-Plex panel was used to measure cytokine levels. Surprisingly, the data revealed that 18 of the 23 cytokines analyzed were significantly downregulated in the hemisphere contralateral to the TBI impacted hemisphere. IL-5, IL-6 and MIP-3a were significantly suppressed in both ipsilateral and contralateral hemispheres of neonatal TBI rats compared to the control rats. A parallel study processing the plasma of the same cohort of neonatal rats revealed no difference in the same cytokines analyzed in the brain tissue, suggesting highly localized cytokine suppression in the brain during early injury. In stark contrast to the reported early pro-inflammatory response exhibited in adult TBI, the present neonatal TBI study demonstrated a reversed cytokine profile of downregulation. These results suggest a robust, immediate anti-inflammatory response mounted by the contralateral hemisphere of the young brain.


Subject(s)
Brain Injuries/immunology , Brain/immunology , Cytokines/metabolism , Animals , Brain/growth & development , Chemokine CCL20/blood , Chemokine CCL20/metabolism , Cytokines/blood , Disease Models, Animal , Down-Regulation , Interleukin-5/blood , Interleukin-5/metabolism , Interleukin-6/blood , Interleukin-6/metabolism , Male , Rats , Rats, Sprague-Dawley , Time Factors
19.
J Neurosci ; 34(1): 313-26, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24381292

ABSTRACT

Traumatic brain injury (TBI) survivors exhibit motor and cognitive symptoms from the primary injury that can become aggravated over time because of secondary cell death. In the present in vivo study, we examined the beneficial effects of human adipose-derived stem cells (hADSCs) in a controlled cortical impact model of mild TBI using young (6 months) and aged (20 months) F344 rats. Animals were transplanted intravenously with 4 × 10(6) hADSCs (Tx), conditioned media (CM), or vehicle (unconditioned media) at 3 h after TBI. Significant amelioration of motor and cognitive functions was revealed in young, but not aged, Tx and CM groups. Fluorescent imaging in vivo and ex vivo revealed 1,1' dioactadecyl-3-3-3',3'-tetramethylindotricarbocyanine iodide-labeled hADSCs in peripheral organs and brain after TBI. Spatiotemporal deposition of hADSCs differed between young and aged rats, most notably reduced migration to the aged spleen. Significant reduction in cortical damage and hippocampal cell loss was observed in both Tx and CM groups in young rats, whereas less neuroprotection was detected in the aged rats and mainly in the Tx group but not the CM group. CM harvested from hADSCs with silencing of either NEAT1 (nuclear enriched abundant transcript 1) or MALAT1 (metastasis associated lung adenocarcinoma transcript 1), long noncoding RNAs (lncRNAs) known to play a role in gene expression, lost the efficacy in our model. Altogether, hADSCs are promising therapeutic cells for TBI, and lncRNAs in the secretome is an important mechanism of cell therapy. Furthermore, hADSCs showed reduced efficacy in aged rats, which may in part result from decreased homing of the cells to the spleen.


Subject(s)
Adipose Tissue/transplantation , Brain Injuries/surgery , Cognition Disorders/surgery , Motor Skills Disorders/surgery , Nerve Degeneration/surgery , Stem Cell Transplantation/methods , Adipose Tissue/cytology , Age Factors , Animals , Brain/metabolism , Brain/pathology , Brain/surgery , Brain Injuries/metabolism , Brain Injuries/pathology , Cells, Cultured , Cognition Disorders/metabolism , Cognition Disorders/pathology , Humans , Infusions, Intravenous , Male , Motor Skills Disorders/metabolism , Motor Skills Disorders/pathology , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Rats , Rats, Inbred F344 , Tissue Distribution/physiology
20.
PLoS One ; 8(12): e81585, 2013.
Article in English | MEDLINE | ID: mdl-24349091

ABSTRACT

Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients.


Subject(s)
Brain Injuries/pathology , Brain/pathology , Cell Proliferation , Stress Disorders, Post-Traumatic/pathology , Animals , Biomarkers/metabolism , Brain/metabolism , Brain/physiopathology , Brain Injuries/metabolism , Brain Injuries/physiopathology , Brain Mapping , Cell Death , Cell Differentiation , Cell Movement , Doublecortin Domain Proteins , Doublecortin Protein , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Inflammation/physiopathology , Ki-67 Antigen/metabolism , Microglia/metabolism , Microglia/pathology , Microtubule-Associated Proteins/metabolism , Neurogenesis , Neurons/metabolism , Neurons/pathology , Neuropeptides/metabolism , Rats , Rats, Sprague-Dawley , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/physiopathology
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