Repeated Stress Induces Dendritic Spine Loss in the Rat Medial Prefrontal Cortex

Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cerebral Cortex (Impact Factor: 8.67). 04/2006; 16(3):313-20. DOI: 10.1093/cercor/bhi104
Source: PubMed


The prefrontal cortex (PFC) plays an important role in higher cognitive processes, and in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Here we examined the effect of repeated restraint stress on dendritic spine number in the medial PFC. Rats were perfused after receiving 21 days of daily restraint stress, and intracellular iontophoretic injections of Lucifer Yellow were carried out in layer II/III pyramidal neurons in the anterior cingulate and prelimbic cortices. We found that stress results in a significant (16%) decrease in apical dendritic spine density in medial PFC pyramidal neurons, and confirmed a previous observation that total apical dendritic length is reduced by 20% in the same neurons. We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses, but may impair these neurons' capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.

Download full-text


Available from: Jason J Radley, Oct 01, 2014
48 Reads
  • Source
    • "A mushroom spine type was identified when its head diameter exceeded 0.6 lm; the remaining spines were classified as " other, " which consisted mainly of stubby spines and filopodia. The values for the numbers of spines at a given distance from the origin of the branch were then averaged; all the neurons from the same animal (four cells from each hemisphere/animal) were averaged for an animal mean (Shors et al., 2004; Radley et al., 2006), and these data were pooled with the mean of the other animals belonging to the same experimental group. The total number of spines corresponded to the sum of spines present along the dendritic length of 80 mm. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic stress promotes cognitive impairment and dendritic spine loss in hippocampal neurons. In this animal model of depression, spine loss probably involves a weakening of the interaction between pre- and postsynaptic cell adhesion molecules, such as N-cadherin, followed by disruption of the cytoskeleton. N-cadherin, in concert with catenin, stabilizes the cytoskeleton through Rho-family GTPases. Via their effector LIM kinase (LIMK), RhoA and ras-related C3 botulinum toxin substrate 1 (RAC) GTPases phosphorylate and inhibit cofilin, an actin-depolymerizing molecule, favoring spine growth. Additionally, RhoA, through Rho kinase (ROCK), inactivates myosin phosphatase through phosphorylation of the myosin-binding subunit (MYPT1), producing actomyosin contraction and probable spine loss. Some micro-RNAs negatively control the translation of specific mRNAs involved in Rho GTPase signaling. For example, miR-138 indirectly activates RhoA, and miR-134 reduces LIMK1 levels, resulting in spine shrinkage; in contrast, miR-132 activates RAC1, promoting spine formation. We evaluated whether N-cadherin/β-catenin and Rho signaling is sensitive to chronic restraint stress. Stressed rats exhibit anhedonia, impaired associative learning, and immobility in the forced swim test and reduction in N-cadherin levels but not β-catenin in the hippocampus. We observed a reduction in spine number in the apical dendrites of CA1 pyramidal neurons, with no effect on the levels of miR-132 or miR-134. Although the stress did not modify the RAC-LIMK-cofilin signaling pathway, we observed increased phospho-MYPT1 levels, probably mediated by RhoA-ROCK activation. Furthermore, chronic stress raises the levels of miR-138 in accordance with the observed activation of the RhoA-ROCK pathway. Our findings suggest that a dysregulation of RhoA-ROCK activity by chronic stress could potentially underlie spine loss in hippocampal neurons. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 05/2015; 93(10). DOI:10.1002/jnr.23602 · 2.59 Impact Factor
  • Source
    • "The medial prefrontal cortex (MPFC) plays an important role in the modulation of behavioural and physiological responses to stressful stimuli. Several studies demonstrated MPFC remodelling following chronic exposure to stressors, and these cellular changes could be implicated in psychiatric disorders (Radley et al. 2004, 2006b, 2008). The ventral portion of the MPFC is comprised of the prelimbic (PL), infralimbic (IL) and dorsal peduncular cortices (Zilles & Wree, 1985; Paxinos & Watson, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: New findings: What is the central question of this study? A brief experience of stress can cause structural remodelling in the infralimbic cortex. In the present study, we addressed the potential role played by opioidergic neurotransmission in the infralimbic cortex in the modulation of stress-evoked autonomic responses. What is the main finding and its importance? Using the restraint stress model, we showed that infralimbic cortex κ-opioid receptors, but not μ- and δ-opioid receptors, modulate stress-evoked cardiovascular responses. The infralimbic cortex (IL) is known to modulate behavioural and physiological responses during aversive situations. We investigated the hypothesis that opioid neurotransmission in the IL modulates the autonomic responses induced in rats subjected to restraint stress (RS). Male Wistar rats (250-280 g) were used. Guide cannulae were implanted bilaterally in the IL for the microinjection of either drugs or vehicle, and a polyethylene catheter was implanted into the femoral artery for recording of mean arterial pressure (MAP) and heart rate (HR) using a computerized acquisition system. Tail temperature was evaluated using a thermal camera. Rats were subjected to RS 10 min after the microinjection of drugs or vehicle into the IL. Exposure to RS evoked hypertension, tachycardia and a reduction in tail temperature. Bilateral microinjections of the non-selective opioid antagonist naloxone into the IL generated an inverted U-shaped dose-inhibition curve on RS-evoked MAP and HR responses. Microinjection of nor-BNI (κ-selective antagonist) reduced the increases in MAP and HR evoked by RS. In contrast, pretreatment of the IL with CTAP (μ-selective antagonist) or naltrindole (δ-selective antagonist) had no effect on the restraint-evoked increases in MAP and HR. None of these treatments altered the reduction in the tail temperature evoked by RS. In conclusion, κ-opioid receptors in the IL modulate pressor and tachycardiac responses caused by RS, suggesting a facilitatory role of this structure in this aversive situation.
    Experimental physiology 01/2015; 100(4). DOI:10.1113/expphysiol.2014.084020 · 2.67 Impact Factor
  • Source
    • "Se encontraron dos resultados distintos. Por un lado, se encontró una reducción en la cantidad de espinas dendríticas presentes en las neuronas en mCPF y, por otro lado, un aumento en el número de ramificaciones dendríticas y de nuevas espinas dendríticas en OFC (Liston et al., 2006; Radley et al., 2006). Los cambios en las conexiones sinápticas generados en estas áreas se acompañaron de disminución en las funciones ejecutivas, tales como déficit en la toma de decisiones, baja autorregulación emocional y disminución en la focalización de la atención. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Grandes esfuerzos han sido llevados a cabo para entender los componentes psicobiológicos del estrés y de algunas de las psicopatologías relacionadas con él, tales como los trastornos de ansiedad (ansiedad generalizada o crisis de pánico) e incluso la depresión. Existen evidencias de que procesos como la neurogénesis y la plasticidad se ven enormemente afectados por muchos factores, entre ellos el estrés. En esta revisión se presentan algunos de los principales conceptos sobre la relación entre estrés, plasticidad y neurogénesis, a los que se ha llegado a partir de investigaciones realizadas –principalmente en modelos animales–, desde hace algunas décadas. Se realizará una diferenciación entre los efectos ocasionados por estrés crónico y agudo, tratando de establecer las interacciones que sobre estos efectos ejercen algunas variables tales como el género o el rango de edad, se enfatizarán los efectos comportamentales para finalmente revisar algunas de las formas de intervención actualmente más usadas para el tratamiento del estrés.
    Universitas Psychologica 09/2014; 13(3):1181-1214. DOI:10.11144/Javeriana.UPSY13-3.eepp · 0.40 Impact Factor
Show more