Opening these black boxes has been difficult To do so would requ

Opening these black boxes has been difficult. To do so would require estimates of activity in many—ideally, all—neurons carrying perceptually relevant signals. Because sensory representations tend to be distributed over large numbers of neurons, such estimates have generally remained elusive (see Kreher et al. [2008] for a notable exception). Here, we take advantage of the well-characterized olfactory system

of fruit flies to relate knowledge of the population representations of odors to behavioral measures of odor discrimination. Flies detect odorous molecules with arrays of ∼50 types of olfactory receptor neuron (ORN) (Couto et al., 2005 and Fishilevich and Vosshall, 2005) whose response spectra are determined by the expression of a single functional odorant receptor (Clyne et al., 1999, Vosshall et al., Topoisomerase inhibitor 1999, Dobritsa et al., 2003 and Hallem et al., 2004). The mean spike rates evoked by 110 odorants in 24 of the ∼50 ORN types of adult flies have been measured (Hallem and Carlson, 2006 and Hallem et al., 2004), providing LDN-193189 concentration a quantitative description of activity in approximately half of the neuronal population at the input stage of the olfactory system. ORN axons segregate by receptor type (Gao et al., 2000 and Vosshall et al., 2000) and transmit signals via separate

synaptic relays, the glomeruli of the antennal lobe, to discrete classes of excitatory projection neurons (ePNs) (Jefferis et al., 2001 and Stocker Mephenoxalone et al., 1990). ePN responses are saturating functions of input from cognate ORNs that scale inversely with total ORN activity (Olsen et al., 2010). Thus, a two-parameter transformation incorporating direct and total ORN activity allows estimation of mean ePN spike rates from measured ORN spike rates. ePNs project to two brain areas: the mushroom

body (MB) and the lateral horn (LH) of the protocerebrum. Innate odor-driven behaviors are thought to rely on circuits of the LH only (Heimbeck et al., 2001), whereas learned behaviors require the MBs (Heisenberg et al., 1985), whose plastic output synapses are the postulated storage sites of learned associations (Heisenberg, 2003). The MBs only receive feedforward excitation from cholinergic ePNs, whereas the LH receives parallel excitatory and inhibitory inputs via ePNs and a functionally uncharacterized group of mostly multiglomerular GABAergic inhibitory PNs (iPNs) (Jefferis et al., 2001, Lai et al., 2008, Okada et al., 2009 and Tanaka et al., 2012). Inhibition has been invoked in many sensory systems as a mechanism for enhancing contrast (Barlow, 1953, Hartline et al., 1956 and Kuffler, 1953), exerting gain control (Barlow, 1961, Olsen et al., 2010, Olsen and Wilson, 2008 and Root et al., 2008), or binding neurons representing different stimulus features in synchrony (Gray et al., 1989, Laurent and Davidowitz, 1994 and Stopfer et al., 1997). It is currently unknown whether iPNs play any of these roles.

NMDA receptors display a characteristic inhibition by extracellul

NMDA receptors display a characteristic inhibition by extracellular Mg2+ (Nowak et al., 1984). Addition of 2 mM Mg2+ had, however, no effect on IR84a+IR8a or IR75a+IR8a

currents measured when the primary charge carrier was Na+ (Figure S4A). We also tested several iGluR antagonists for their influence on IR-dependent currents, including two NMDA pore blockers, memantine and MK-801 (Kashiwagi et al., 2002), and an AMPA and Kainate receptor blocker, philanthotoxin (Jones et al., 1990 and Ragsdale et al., 1989). None of these had effects on either IR84a+IR8a or IR75a+IR8a currents, except for memantine, which inhibited phenylacetaldehyde-induced IR84a+IR8a currents with a half maximal inhibitory concentration (IC50) of 39 ± 9 μM (Figure S4B), a value that is ∼40 times the IC50 of memantine for NMDA receptors (Parsons et al., 2008). Antagonists for several other classes of ion channel, including amiloride, Cd2+, tetraethylammonium (TEA), selleck kinase inhibitor and ruthenium red, had mostly modest effects on IR84a+IR8a or IR75a+IR8a currents, even at high concentrations (Figure S4B). Notably, while ruthenium red slightly inhibited IR84a+IR8a currents, it enhanced IR75a+IR8a current

amplitudes (Figure S4B). Together, these experiments distinguish IRs pharmacologically from both iGluRs and other classes of ion channel, and further highlight the physiological differences between different IR complexes. To understand the molecular basis for the functional heterogeneity JAK inhibitor of IR84a+IR8a and IR75a+IR8a, we compared the sequence of the putative ion channel pore domains of IR84a, IR75a, and IR8a with those of iGluRs. While this region is highly conserved in iGluRs, individual IRs bear a large number of amino acid substitutions (Figure 6B). This sequence divergence may account for the observed insensitivity of IRs to iGluR pore blockers as well as the pharmacological differences between IR84a+IR8a and IR75a+IR8a (Figures 6A, S4A, and S4B). We focused on residues aligned with a glutamine that controls Ca2+ permeability in iGluRs (Dingledine et al., 1992) (Figure 6B). In GluA2, RNA editing-regulated

substitution of this glutamine to arginine renders channels Ca2+-impermeable of (Hume et al., 1991 and Liu and Zukin, 2007). While IR75a contains an isoleucine (I388) in this position, IR84a retains a glutamine (Q401) (Figure 6B). We hypothesized that this residue might account for the difference in Ca2+ conductance mediated by IR75a+IR8a and IR84a+IR8a channels (Figure 6A). To test this, we generated an IR84aQ401R mutant receptor, which we predicted to lack Ca2+ permeability. IR84aQ401R+IR8a expressing oocytes showed similar Na+ current amplitudes (Figure 6C) and phenylacetaldehyde concentration responses as the wild-type receptors (Figure 6D). Importantly, IV curve measurements revealed that IR84aQ401R+IR8a-dependent conductance of monovalent cations was unchanged compared with the wild-type receptors, but that Ca2+-dependent conductance was abolished (Figure 6E).

All subjects were rearfoot strikers (visually inspected beforehan

All subjects were rearfoot strikers (visually inspected beforehand while running in their own TRS), free of any injury for at least 6 months prior to the study, recreational athletes (different sports) and aged between 18 and 55 years. None of the subjects had a history of or experience with BF running. The study complies with the Declaration of Helsinki, and all subjects signed a written consent

form prior to the testing procedures. Three-dimensional kinematics was recorded with a six-camera infrared system (ViconPeak, MCam, M1; Oxford, UK) at a sampling frequency of 250 Hz. All runners ran BF on a 20-m EVA foam runway (shore hardness approx. 40), and shod wearing Nike Free 3.0 (shore hardness approx. 40) on a 20-m tartan indoor track. The height of the foam runway was 10 mm, comparable to the midsole/outsole

this website heel height of MRS. The order of running conditions was randomized. Prior to the recorded measurements, sufficient time was allowed for the subjects to familiarize themselves with the laboratory setup and to get used to the CH5424802 running speed and surface to enable an individual running style. All subjects ran with a controlled running speed of 11 km/h monitored using a photoelectric barrier, and a running speed between 10.5 km/h and 11.5 km/h was accepted. The test speed of 11 km/h was chosen as this is an average running speed in recreational athletes, both for men and women. Touch-down was visually inspected to find out if subjects landed on the rearfoot or on the mid/forefoot. Eighteen markers were placed on each subject according to the recommendations of the International Society of Biomechanics,15 marking both shanks (medial and lateral tibia plateau, tibial tuberosity, medial tibial crest, lateral and medial malleoli), the foot Thymidine kinase (lateral, medial, and posterior calcaneus), and the hallux. Rearfoot markers were screwed to a short thread (∼1 cm) and screw sockets were attached to customized flexible plastic disks placed on the calcaneus to ensure their visibility and identical placement for both BF and shod conditions (Fig. 1) and to ensure a good fit of the markers

with respect to the foot. Joint excursions were quantified by calculating Cardan angles according to Söderkvist and Wedin16 with the foot segment rotating with respect to the shank segment (ankle dorsiflexion/plantarflexion, rearfoot inversion/eversion), or with respect to the global coordinate system (tibial rotation, sagittal ankle, and frontal rearfoot motion). Further, the first rotation was computed around the sagittal axis (dorsiflexion/plantarflexion), the second rotation around the frontal axis (inversion/eversion) and finally, the third rotation was computed around the transversal axis (external/internal rotation). For the subsequent analysis, stance phase was detected according to Maiwald et al.17 and subsequently normalized to 100 data points which equal 100% of stance phase (%SP); swing phase was neglected.

, 2006) This unique structural characteristic also supports the

, 2006). This unique structural characteristic also supports the possibility of an autocatalytic mechanism in ADAM10 ectodomain shedding. The ADAM10

LOAD mutations in the prodomain may interfere with the ectodomain shedding by decreasing either the enzyme activity (protease domain) or substrate accessibility (cysteine-rich domain) of ADAM10. In the ADAM10 transgenic mice, the prodomain and catalytic-site mutations decrease α-site cleavage of APP (less APP-CTFα). Notably, reduced α-secretase activity was accompanied by an increase in β-secretase processing 3-Methyladenine cost of APP (higher levels of APP-CTFβ, sAPPβ, and Aβ). Concordantly, a missense mutation, which was recently found in an early-onset dementia family precisely at the APP α-secretase cleavage site (K16N), led to a decrease in APP-CTFα coupled with increases in levels of APP-CTFβ Cisplatin mw and Aβ (Kaden et al., 2012). Inverse effects have been reported in mice with altered β-secretase gene expression. BACE1 KO mice produced elevated APP-CTFα (Luo et al., 2001), and BACE1 transgenic mice revealed reduced APP-CTFα with increased APP-CTFβ and

sAPPβ (Lee et al., 2005). Although several cell-based studies produced inconsistent results with regard to these alternative cleavages (Colombo et al., 2012), studies using genetically modified mice have consistently shown the presence of competition between α- and β-secretases on APP processing in the brain (Lee et al., 2005, Luo et al., 2001 and Postina et al., 2004). Remarkably,

while ADAM10-WT overexpression in Tg2576 mice decreased ∼35% of Aβ levels at 3 months old, the impact was dramatically magnified at 12 months, at which point Aβ40 and Aβ42 levels were decreased by more than 99% in the Phosphatidylinositol diacylglycerol-lyase ADAM10-WT mice (Figure 3). LOAD mutant forms of ADAM10, which possess attenuated α-secretase activity (60%–70% of WT), did not produce notable decreases in Aβ levels in 3-month-old double-transgenic mice. However, Aβ levels were dramatically downregulated (∼95%) in the brains of 12-month-old double transgenics, as compared to Tg2576 control. The robust decrease in Aβ plaque load was maintained up to 18 to 20 months old (Figure 4). This profound impact on plaque load by ADAM10 in older brains is consistent with a previous report that employed transgenic mice overexpressing bovine ADAM10 and human APP London mutation (Postina et al., 2004). In addition to the potential direct cleavage of Aβ by ADAM10 (Lammich et al., 1999), this increased effect in older mice might be the result of accumulated production and deposition of excess Aβ in brains. As the half-life of Aβ in brains is only ∼2 hr (Cirrito et al., 2003), changes in Aβ generation rate would greatly affect the accumulation and deposition of Aβ over several months in the brains of APPswe-overexpressing Tg2576 mice.

Failure to habituate to physiological stimuli in the interictal p

Failure to habituate to physiological stimuli in the interictal period is well known. For example, abnormal habituation to stimuli is observed in migraine (Afra et al., 2000, Coppola et al., 2009, Schoenen et al., 2010 and Wang and Schoenen, 1998), although in some types of migraine (viz., familial hemiplegic migraine), there is increased habituation (Hansen et al., 2011). Although the underlying mechanism(s) is unclear, it has been proposed that lack of habituation in migraine may reflect increased neuronal excitability, decreased inhibition, or decreased preactivation levels. In migraine, both

central (brain) and peripheral processes are altered. The interictal PF-06463922 purchase brain is hyperexcitable in migraine, and there is a lack of habituation in neuronal information processing (Burstein et al., 2010, Chen et al., 2011 and Coppola et al., 2009). This concept applies to both migraine chronification and migraine regression. Chronification of migraine, in which headaches become more frequent (>14 headache days/month), is a result of abnormal repeated stressors and use or overuse of certain medications (e.g., triptans, opioids) and is likely to be exacerbated by genetic factors. Chronification of migraine is suggestive of progressive maladaptation of the brain. Elimination of stressors may diminish

chronification, as reported learn more in women whose menstrual periods were effectively controlled by hormonal preventives, leading to a reversal from chronic migraine to episodic migraine in nearly 60% of individuals (Calhoun and Ford, 2008). Similarly, exercise can diminish the frequency of migraine attacks (Malpass, 2011). It should

be noted that although there are no known mechanisms for migraine transformation, a number of defined stressors may contribute to this, including childhood abuse (Tietjen and Peterlin, 2011), socioeconomic status/social stress (Chyu and Upchurch, 2011), and posttraumatic stress disorder (PTSD) (Peterlin et al., 2011). Given the above points, we argue that migraine is perhaps an “ideal” brain allostatic load disease model. The allostatic load associated with migraine arises from the disruption of behavior and dysregulation much of adaptive physiological systems that appears with severe headache pain and subsequent responses. Because migraine affects behavioral and systemic health for a significant portion of the patients’ lives (>15 years [Kelman, 2006]), it is a compelling model of increased allostatic load (McEwen and Gianaros, 2011). If studied more systematically with this approach in mind, such thinking may provide new approaches to modulating or treating the condition, including the definition of a migraine allostatic load index (Juster et al., 2011). What differentiates tension-type headaches (TTH) (http://ihs-classification.

, 2001 and Pantoja et al , 2007) Potential exceptions are in V1

, 2001 and Pantoja et al., 2007). Potential exceptions are in V1 cortex in the visual system (Shuler and Bear, 2006), the brainstem in the gustatory system (Chang and Scott, 1984), and within the olfactory system, where learning-induced changes occur within the olfactory bulb (OB) one or two synapses away from the sensory neuron (Friedrich et al., 2004, Gao and Strowbridge, 2009, Gray et al., 1986, Kay and Laurent, 1999, Nissant et al., 2009 and Wilson and Leon, 1988). However, it is not clear whether learning-related plasticity in these early circuits represents a modulation in the circuitry to enhance discrimination or whether it plays a more dynamic role and actively contributes to the

encoding of stimulus value (Kay and Laurent, 1999). Please note that when we refer to odor value, we do not exclude Selleck 3-deazaneplanocin A Proteasome inhibitor drugs the possibility that the circuit may carry information on a related reward signal (Wallis and Kennerley, 2010). Olfactory sensory neurons transform information about the chemical structure of an odor into neuronal activity and transmit information synaptically to second-order cells, including the mitral cells (MCs) (Shepherd et al., 2004 and Tan et al., 2010). Interneuron circuits within the OB modulate MC firing and likely provide contrast

enhancement (Aungst et al., 2003, Mori et al., 1999 and Shepherd et al., 2004), and learning modifies activity of MCs through plasticity that is likely caused by feedback from neuromodulatory systems and centrifugal input from the olfactory cortex (OC) back into the OB (Doucette and Restrepo, 2008, Gao and Strowbridge, 2009, Mandairon and Linster, 2009, Restrepo et al., 2009 and Wilson and Mainen, 2006). Interestingly, studies of odor-induced oscillatory field potentials in olfactory discrimination tasks suggest the involvement aminophylline of changes in synchronous firing between neurons in the OB circuit in learning in vertebrates (Gray et al., 1986, Kay and Beshel, 2010 and Martin et al., 2006). In addition, MCs are hypothesized to aid in synthesis of simultaneously detected odor features through

synchronized firing and convergence on neurons in OC (Kashiwadani et al., 1999 and Mori et al., 1999), which has been supported by experiments in invertebrates (Stopfer et al., 1997). Studies in vertebrates are consistent with the claim that synchronous firing of MCs increases the probability of driving target OC neurons (Franks and Isaacson, 2006 and Luna and Schoppa, 2008). However, direct evidence for synchronized firing of MCs in vertebrates is limited to a measurement of synchrony in anesthetized animals (Kashiwadani et al., 1999) that was not replicated (Egaña et al., 2005). Thus, the precise role of synchronized MC firing in transfer of olfactory information, in learning of olfactory stimulus/reward association, or in both is not well understood.

Body temperature was continuously monitored by a rectal thermomet

Body temperature was continuously monitored by a rectal thermometer and maintained at 37°C ± 0.5°C by placing the animal on a heating pad. For experiments on head-fixed, fully awake rats, animals were remounted in a second frame above a spherical treadmill (air-supported polystyrol ball with 300 mm diameter; Jetball, PhenoSys; see Dombeck et al., 2007). In this system, animals were able to groom, rest, or run, with maximal linear velocities of 40 cm s−1.

Rats were allowed to recover from anesthesia and adapt to the recording device for at least 3 hr. The insertion PARP assay of the recording electrodes was performed under a light and brief inhalation anesthesia, applying 0.2%–0.4% isoflurane (Forane; Abbott) via a ventilation

mask for <5 min. Anesthesia was terminated immediately after the WC configuration was established, and data acquisition was started ∼10 min later. Panobinostat Analgesia was ensured by i.p. application of 50 mg/kg metamizole (Sanofi-Aventis; in strict accordance with animal regulations). In awake animals, all sensors were removed to minimize stress. Vigilance of animals was judged by high muscle tone, movement of whiskers, tail, and limbs, the presence of postural reactions, and locomotor patterns. Animals were able to move on the spherical treadmill freely but characteristically from showed a low level of motor activity under our conditions, with long periods of immobility/lingering and short periods of movement, as expected during exploration of a relatively new environment (Whishaw and Kolb, 2005). The total recording time was 5–30 min (including periods of both immobility

and moderate motor activity). Robust theta and gamma activity was recorded in the LFP under these behavioral conditions. However, our theta peak frequency corresponded to the lower part of the previously defined theta frequency range, presumably due to the inclusion of both immobility and moderate motor activity periods in our analysis (Bland, 1986 and Buzsáki, 2002). Pipettes for both WC and LFP recording were fabricated with a Brown-Flaming micropipette puller (either P-97 or P-1000; Sutter Instrument), using 1 mm outer diameter and 0.5 mm inner diameter borosilicate glass capillaries (Hilgenberg). Pipettes used for patch-clamp recording had tip resistances of 4–7 MΩ. For current-clamp experiments, pipette solution contained 134 mM K-gluconate, 2 mM KCl, 10 mM EGTA, 2 mM MgCl2, 2 mM Na2ATP, 10 mM HEPES, and 3 mg ml−1 biocytin (pH adjusted to 7.28 with KOH). For voltage-clamp experiments with EPSCs, a pipette solution containing 134 mM K-methanesulfonate, 2 mM KCl, 10 mM EGTA, 2 mM MgCl2, 2 mM Na2ATP, 10 mM HEPES, 3 mg ml−1 biocytin, and 5 mM QX-314 was used.

We will demonstrate that transdiagnostic patterns of dysconnectiv

We will demonstrate that transdiagnostic patterns of dysconnectivity underlie transdiagnostic patterns of psychiatric symptoms, and may explain why comorbidity among diagnostic categories is so frequently observed. Third, we will propose that genetic and environmental risk factors for mental illness induce susceptibility to broad domains of psychopathology, rather than discrete categorical disorders, because selleck compound they disrupt core connectivity circuits in ways that necessarily produce transdiagnostic symptoms (Figure 1; Figure 2). To illustrate this point, we will show that several genetic variants that induce

broad susceptibility to mental illness perturb specific connectivity circuits to engender disorder-spanning symptoms. Brain information processing can be conceptualized along two organizational principles: functional segregation and functional integration (Friston, 1994). Functional segregation refers to specialized processing that takes place in “local” populations of neurons, often defined by common functional properties selleck chemicals (for example, language processing in neurons in the left inferior frontal gyrus). Such specialization extends even beyond the processing of stimulus categories or external stimulus features to encompass motivationally salient contextual elements of a stimulus, for example neuronal encoding of internal goal representations

in the dorsolateral prefrontal cortex (Miller and Cohen, 2001). However, successful execution of even simple behaviors requires that the specialized outputs of each of these functionally segregated neuronal populations be integrated. Connectivity makes this functional integration possible. The anatomical framework underlying connectivity has been the subject of several excellent recent Tryptophan synthase reviews (Johansen-Berg and Rushworth, 2009 and Sporns, 2011). Here, we focus on the functional mechanisms that permit integration between specialized processing nodes. Connectivity mediates the convergence of manifold computations about external sensory stimuli and

internal states, and serves a vital enabling function through which such computations are ultimately able to influence behavior. Patterns of connectivity across regions are dynamically arranged according to moment-to-moment changes in the array of available external sensory inputs, internal states, and response options. The complexity inherent in this constant adaptive reconfiguration of functional integration between regions would appear to provide many opportunities for failure, each accompanied by a characteristic set of cognitive, emotional, motivational and social consequences, or symptoms. It has long been noted that alterations in circuit-level connectivity can have a more pronounced impact on behavior and psychopathology compared to disruptions in regional activity alone.

It would be a pity if, in their justifiable enthusiasm for this p

It would be a pity if, in their justifiable enthusiasm for this powerful tool, social psychologists subtly shifted their research programs to problems that are amenable to brain localization or shifted their theoretical language to constructs

that are localizable. –Willingham and Dunn (2003) Certainly, it is currently hard Dolutegravir price to see how basic computations implemented in small assemblies of neurons can be related to, say, phenomena such as stereotyping from social psychology. This threat of reductionism, properly a threat of elimination of concepts associated with more macroscopic levels of description, is however not unique to social neuroscience but pervades the study of all of cognition. As in the general case, the way forward in social neuroscience is simple enough: both micro- and macroscopic levels of analysis, as well as the development of concepts associated with each of them, should proceed in tandem. Tension can be relieved if we realize that there is no “fundamental” level of description, or ontology of concepts, that should have priority over any other; we would favor a pragmatic view that incorporates new concepts simply

on the basis of their utility. Each level of description has concepts EPZ-6438 that are the most useful for that level of description. Of course, the levels describe a single reality, and so the concepts must somehow relate to one another. But reduction or elimination is not needed: what is needed is communication, so that those working at different levels of analysis Amisulpride can appreciate, and understand, work at different levels. We do not so much need a single language, as we need people who can speak several languages and translate easily between them. Nowhere is the challenge of translating across languages more apparent than in comparative social neuroscience. People with backgrounds in neuroethology, animal behavior, or cellular neurobiology typically do not discuss science with those doing fMRI in humans. As we noted

at the beginning, the two main societies for social neuroscience in fact reflect this rift: there are those studying humans (generally with fMRI) on the one hand and those studying nonhuman animals (generally not with fMRI) on the other. It is interesting to note that the species differences parallel the different methods used. We most strongly believe that these differences need communication. Comparisons must be made across species, and the findings in particular from fMRI studies in humans need to be related to data from other species and obtained with other methods (see Adolphs and Anderson, 2013). However, it is one thing to recommend this, and another to spell out in more detail why and how.

The acute administration did not alter the mitochondrial complex

The acute administration did not alter the mitochondrial complex II–III activity in the prefrontal Libraries cortex (F(3–16) = 0,759; p = 0,53 Fig. 4C), amygdala (F(3–16) = 2.451; selleck p = 0.10 Fig. 4C) and hippocampus (F(3–16) = 1.519; p = 0,24 Fig. 4C). The chronic treatment increased the mitochondrial complex II-III activity in the prefrontal cortex (F(3–15) = 4.175; p = 0,03 Fig. 4C) and hippocampus (F(3–13) = 10.168; p = 0.001 Fig. 4C) with imipramine at the dose of 30 mg/kg and in the amygdala (F(3–14) = 10.512; p = 0.001 Fig. 4C) with all treatments, but did not alter in the prefrontal cortex (F(3–15) = 4.175; p > 0.05 Fig. 4C) and in the hippocampus

(F(3–13) = 10.168; p > 0.05 Fig. 4C). The acute administration increased Selleck Dabrafenib the mitochondrial complex IV activity in the hippocampus (F(3–13) = 18.471; p < 0,001 Fig. 4D) with all treatments, compared with saline, but did not alter in the prefrontal cortex (F(3–12) = 0.828; p = 0.50 Fig. 4D) and amygdala (F(3–11) = 4,514; p = 0,27 Fig. 4D). The chronic treatment did not alter the mitochondrial complex IV activity in the prefrontal cortex (F(3–13) = 0.689; p = 0.57 Fig. 4D), amygdala (F(3–16) = 3.666; p = 0.35 Fig. 4D) or hippocampus (F(3–11) = 2.317; p = 0.13 Fig. 4D). The acute treatment decreased the Bcl-2 protein levels in the

prefrontal cortex (F(3–12) = 106.818; p < 0,001 Fig. 5A) and in the hippocampus (F(3–12) = 265,226; p < 0,001 Fig. 5A) with imipramine at the dose of 30 mg/kg and lamotrigine at the dose of 20 mg/kg, and also in the amygdala (F(3–12) = 87.304; p < 0.001 Fig. 5A) with all treatments, compared with saline. The chronic treatment decreased the Bcl-2 protein levels in the prefrontal cortex (F(3–12) = 310.093; p < 0.001 Fig. 5A), amygdala (F(3–12) = 238.818; p < 0.001

Fig. 5A) and hippocampus (F(3–12) = 557.669; p < 0.001 Fig. 5A) with all treatments. The acute treatment why increased the AKT protein levels in the prefrontal cortex (F(3–12) = 49.088; p = 0.000 Fig. 5B) with imipramine at the dose of 30 mg/kg, in the amygdala (F(3–12) = 70.335; p < 0.001 Fig. 5B) with lamotrigine at the dose of 20 mg/kg and in the hippocampus (F(3–12) = 21.011; p = 0.009 Fig. 5B), with imipramine at the dose of 30 mg/kg and with lamotrigine at the dose of 20 mg/kg, compared with saline. The acute treatment also decreased the AKT protein levels in the amygdala with imipramine at the dose of 30 mg/kg (F(3–12) = 70.335; p = 0.04 Fig. 5B) and in the hippocampus with lamotrigine at the dose of 10 mg/kg (F(3–12) = 21.011; p = 0.04 Fig. 5B). The chronic treatment increased the AKT protein levels in the prefrontal cortex (F(3–12) = 121.938; p < 0,001 Fig.