Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade

Tomizawa, Kazuhito; Iga, Norichika; Lu, Yun; Moriwaki, Akiyoshi; Matsushita, Masayuki; Li, Shengtian; Miyamoto, Osamu; Itano, Toshifumi; Matsui, Hideki

doi:10.1038/nn1023

Cited by 326 publications

(278 citation statements)

References 37 publications

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“…Indeed, OT has been shown to increase spike output [89][90][91] and facilitate synaptic long-term potentiation [92][93][94] and our data suggest an intrinsic mechanism that may underlie shifts in synaptic efficacy and excitatory/inhibitory balance found in brain regions where OT is critical for myriad social behaviors 67,74,90,95 . Intrinsic properties are shaped by ion channels.…”

Section: Discussionmentioning

confidence: 54%

Insular Cortex Mediates Approach and Avoidance Responses to Social Affective Stimuli

Rogers

Varela

Gribbons

et al. 2017

Preprint

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Social animals detect the affective states of others and utilize this information to orchestrate appropriate social interactions. Social affective behaviors include cooperation, reproductive acts and avoiding sick individuals. In a social affective behavioral test in which experimental adult male rats were given the choice to interact with either naive or stressed conspecifics, the experimental rats demonstrated both approach and avoidant behaviors towards the conspecific, depending upon the age of the conspecific; experimental adult rats approached the stressed juvenile but avoided the stressed adult. Optogenetic inhibition of the insular cortex, a region anatomically positioned to contribute to social cognition, disrupted these behaviors. Receptors for the social nonapeptide oxytocin (OT) are found in high density within the insular cortex and here oxytocin increased intrinsic excitability and synaptic efficacy in acute insular cortex slices. Blockade of oxytocin receptors (OTRs) in the insula eliminated the effect of conspecific stress on approach behavior, while insular administration of OT recapitulated the behaviors typically observed in response to stressed conspecifics. Network analysis using Fos immunoreactivity identified functional connectivity between the insular cortex and the network of regions involved in social decision making. These results implicate insular cortex as a novel target of OT and suggest that insula is a key component in the circuit underlying age-dependent social responses to stressed conspecifics.Social animals, including humans, have an enormous repertoire of behavioral expressions that provide for the transmission of one's affective state to other members of the group 1-3 . Sensory and perceptive systems in the "social decision-making network" (SDMN) which consists of the social brain network 4 and the mesolimbic reward system 5 allow one to appraise these social stimuli and integrate them with past experiences, situational, and somatic factors to shape specific behavioral responses 6 . In addition to the SDMN, growing evidence implicates insular cortex in responding to socioemotional stimuli in humans. When tasked to identify the emotion of another from a facial expression, or to observe another suffer a painful stimulation, a reliable neural correlate is relative increase in the blood oxygen level dependent (BOLD) signal in the insular cortex 7,8 . Accordingly, emotion recognition and empathic deficits have been reported among individuals with insular cortex lesions [9][10][11][12] . Empathic processes are also disrupted in autism spectrum 1 Department of Psychology, Boston College, Chestnut Hill, MA 02467, USA 2 These authors made equal contributions to this work. *Corresponding Author: John P. Christianson, Department of Psychology, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467 USA, Email: j.christianson@bc.edu, Phone: +1-617-552-3970.A note about the preprint. This manuscript was submitted to bioRxiv.org after multiple rounds of peer review. The manuscrip...

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Section: Discussionmentioning

confidence: 54%

Insular Cortex Mediates Approach and Avoidance Responses to Social Affective Stimuli

Rogers

Varela

Gribbons

et al. 2017

Preprint

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“…Further, the MAPK pathway has been demonstrated to be integral to progestins 0 functional effects; blocking MAPK attenuates the intracellular actions of P 4 or membrane actions of 3a,5a-THP to enhance sexual behavior among rats (González-Flores et al 2004, Acosta-Martínez et al 2006. Tomizawa et al (2003) have found that MAPK inhibition also attenuates LTP in multiparous mouse hippocampal slices. These data suggest that signal transduction factors are important in steroid actions and may, in part, underlie some functional cognitive performance changes associated with endogenous E 2 and progestin elevations.…”

Section: Discussionmentioning

confidence: 98%

“…The resulting endocrine milieu, as well as limbic morphology and function, are altered following pregnancy, parturition, and/or pup rearing (Featherstone et al 2000, Tomizawa et al 2003, Pawluski & Galea 2006. First, oxytocin associated with motherhood enhances longterm potentiation (LTP) of hippocampal tissue slices in culture and central infusions of oxytocin enhance longterm spatial memory in virgin mice (Tomizawa et al 2003). Second, hippocampal spinal density is increased in pregnant compared with non-pregnant rats and is also altered by postpartum mothering (Kinsley et al 2006, Pawluski & Galea 2006.…”

Section: Introductionmentioning

confidence: 99%

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

Paris¹,

Frye²

2008

Reproduction

114

105

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Ovarian hormone elevations are associated with enhanced learning/memory. During behavioral estrus or pregnancy, progestins, such as progesterone (P 4 ) and its metabolite 5a-pregnan-3a-ol-20-one (3a,5a-THP), are elevated due, in part, to corpora luteal and placental secretion. During 'pseudopregnancy', the induction of corpora luteal functioning results in a hormonal milieu analogous to pregnancy, which ceases after about 12 days, due to the lack of placental formation. Multiparity is also associated with enhanced learning/memory, perhaps due to prior steroid exposure during pregnancy. Given evidence that progestins and/or parity may influence cognition, we investigated how natural alterations in the progestin milieu influence cognitive performance. In Experiment 1, virgin rats (nulliparous) or rats with two prior pregnancies (multiparous) were assessed on the object placement and recognition tasks, when in high-estrogen/P 4 (behavioral estrus) or low-estrogen/P 4 (diestrus) phases of the estrous cycle. In Experiment 2, primiparous or multiparous rats were tested in the object placement and recognition tasks when not pregnant, pseudopregnant, or pregnant (between gestational days (GDs) 6 and 12). In Experiment 3, pregnant primiparous or multiparous rats were assessed daily in the object placement or recognition tasks. Females in natural states associated with higher endogenous progestins (behavioral estrus, pregnancy, multiparity) outperformed rats in low progestin states (diestrus, non-pregnancy, nulliparity) on the object placement and recognition tasks. In earlier pregnancy, multiparous, compared with primiparous, rats had a lower corticosterone, but higher estrogen levels, concomitant with better object placement performance. From GD 13 until post partum, primiparous rats had higher 3a,5a-THP levels and improved object placement performance compared with multiparous rats.

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“…Although we may infer that E 2 and/or progestins during pregnancy influence cognitive performance, 1 st trimester rats did not have enhanced performance in this task, which may be due to effects of the many pregnancy hormones that are changing at this time. Prolactin, oxytocin, and glucocorticoids are all elevated during pregnancy in rats, are known to influence brain structures, and may be involved in the modulation of spatial cognition (Grattan, 2002;Oitzl et al, 1998;Roozendaal et al, 1996;Shingo et al, 2003;Tomizawa et al, 2003). For that reason, it is essential to examine effects on cognitive performance of both endogenous variations in hormones and effects of systemic hormone-replacement.…”

Section: Discussionmentioning

confidence: 99%

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Frye

Duffy

Walf

2007

Neurobiology of Learning and Memory

216

219

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Steroid modulation of cognitive function has focused on estrogen (E 2 ), but progestins naturally covary with E 2 and may also influence cognitive performance. Spatial performance in the object placement task over endogenous hormonal states in which E 2 and progestins vary, and when E 2 and/ or progestins were administered, was examined. Experiment 1: Rats in proestrus or estrus had significantly better performance in the object placement task than did diestrous rats. Experiment 2: Rats in the third trimester, post-partum, or lactation exhibited significantly better performance in the object placement task than did rats in the first trimester. Experiment 3: Ovariectomized (ovx) rats administered 17β-estradiol (0.9 mg/kg, subcutaneously (sc), progesterone (P; 4 mg/kg, sc), or E 2 and P, immediately after training in the object placement task, performed significantly better when tested 4 hours later, than did control rats administered vehicle (sesame oil 0.2 cc). Experiment 4: Ovx rats administered E 2 or P with a one and a half hour delay after training in the object placement task, did not perform differently than vehicle-administered controls. Experiment 5: Ovx rats administered post-training E 2 , which has a high affinity for both E 2 receptor (ER)α and β isoforms, or propyl pyrazole triol (PPT; 0.9 mg/kg, sc), which is more selective for ERα than ERβ, had significantly better performance in the object placement task than did rats administered vehicle or diarylpropionitrile (DPN; 0.9 mg/kg, sc), an ERβ selective ligand. Experiment 6: Ovx rats administered P, or its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP; 4 mg/kg, sc), immediately post-training performed significantly better in the object placement task than did vehicle control rats. Thus, performance in the object placement task is better when E 2 and/or P are naturally elevated or when E 2 , the ERα selective ER modulator PPT, P, or its metabolite, 3α,5α-THP, are administered post-training.

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Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade

Cited by 326 publications

References 37 publications

Insular Cortex Mediates Approach and Avoidance Responses to Social Affective Stimuli

Insular Cortex Mediates Approach and Avoidance Responses to Social Affective Stimuli

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

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