To take the example of dopaminergic involvement in depression, one could begin to deconstruct this idea by pointing out that “anhedonia” in depression is often misinterpreted or mislabeled by clinicians (Treadway and Zald, 2011). Several studies show that depressed people often learn more have a relatively normal self-rated experience of encounters with pleasurable stimuli and that, over and above any problems with the experience of pleasure, depressed people appear to have impairments in

behavioral activation, reward-seeking behavior, and exertion of effort (Treadway and Zald, 2011). Indeed, most depressed people suffer from a crippling constellation of motivational impairments that include psychomotor retardation, anergia, and fatigue (Demyttenaere et al., 2005; Salamone et al., 2006), and considerable evidence implicates DA in these symptoms (Salamone et al., 2006, 2007). These observations, coupled with the literature indicating that there is not a simple correspondence between DA activity and hedonic experience (e.g., Smith et al., 2011) and the studies linking DA to behavioral activation Ferroptosis tumor and exertion of effort (Salamone et al., 2007;

see discussion below), lead one to conclude that dopaminergic involvement in depression seems to be more complicated than the simple story would have allowed. Similarly, it is clear that a substantial body of research on drug dependence and addiction does not comply with the traditional tenets of the DA hypothesis of reward. Several studies have shown that blockade of DA

receptors or inhibition of oxyclozanide DA synthesis does not consistently blunt the self-reported euphoria or “high” induced by drugs of abuse (Gawin, 1986; Brauer and De Wit, 1997; Haney et al., 2001; Nann-Vernotica et al., 2001; Wachtel et al., 2002; Leyton et al., 2005; Venugopalan et al., 2011). Recent research has identified individual differences in behavioral patterns shown by rats during Pavlovian approach conditioning, which are related to the propensity to self-administer drugs. Rats that show greater response to conditioned cues (sign trackers) display different patterns of dopaminergic adaptation to training as compared to animals that are more responsive to the primary reinforcer (goal trackers; Flagel et al., 2007). Interestingly, the rats that show greater Pavlovian conditioned approach to an appetitive stimulus and show greater incentive conditioning to drug cues, also tend to show greater fear in response to cues predicting shock and greater contextual fear conditioning (Morrow et al., 2011). Additional research has challenged some long held views about the neural mechanisms underlying addiction, as opposed to the initial reinforcing characteristics of drugs.

Similarly, in clones homozygous for milton92, a null mutation ( Glater et al., 2006), mitochondria are increased in neuronal soma but are unchanged in length ( Figure S1A). Further, reduction of miro function does not alter mitochondrial morphology in the presence of transgenic tau but is instead associated GABA receptor inhibition with increased numbers of both normal and elongated mitochondria in the neuronal cell bodies, as well as enhancement of tau neurotoxicity ( Figures S1D and S1E). Thus, elongation of mitochondria in tau transgenic animals does not appear to be a secondary effect of axonal transport defects. We next determined if tau expression can alter mitochondrial

morphology in vertebrate neurons. We used a murine model of tauopathy, rTg4510, in which human tau carrying the FTDP-17 linked P301L mutation is expressed using the CaMKIIα promoter (Ramsden et al., 2005; Santacruz et al.,

2005). To visualize mitochondria selleck screening library in histologic sections from these transgenic mice, we performed immunofluorescent staining for ATP synthase. We observe round to modestly tubular mitochondria in hippocampal pyramidal neurons of control mice (Figure 1B, control, arrowheads). In contrast, mitochondria specifically in hippocampal pyramidal neurons, a vulnerable cell population in these tau transgenic mice, have elongated morphology (Figure 1B, tau, arrowheads). Quantitative analysis reveals a significant increase in mean mitochondrial length in hippocampal neurons from tau transgenic mice (Figure 1B, ADP ribosylation factor graph). We observe similar mitochondrial elongation in a second murine model of tauopathy, K3, in which the FTDP-17-associated mutant form of tau carrying the K369I mutation is expressed under the control of the mThy1.2 promoter

(Ittner et al., 2008). Mitochondrial elongation is prominent in frontal cortical neurons, which express high levels of tau in these animals (Figure S1F). Three-dimensional reconstruction of confocal fluorescence Z-stacks captured from Drosophila and murine neurons affords a more detailed view of the elongated morphology and interconnected organization of mitochondria induced by human tau expression ( Movies S1, S2, S3, and S4). To determine if toxicity of tau to postmitotic neurons is influenced by the mitochondrial elongation we observe in animal models, we manipulated the mitochondrial dynamics machinery genetically. We focused on DRP1 and MARF (the fly homolog of mammalian MFN) and increased and decreased expression of each protein. To increase net mitochondrial fission levels, we overexpressed DRP1 and decreased levels of MARF using transgenic RNAi. These modifications significantly reduce mitochondrial length in tau transgenic flies (Figure 2A). Importantly, normalization of mitochondrial length is accompanied by significant rescue of neurotoxicity, as monitored with TUNEL staining to identify dying neurons (Figure 2B).

, 1994). Electrophysiological and electron

microscopic studies have also shown extensive local synaptic interactions among basal forebrain neurons (Momiyama and Zaborszky, 2006; Zaborszky and Duque, 2003). This raises the possibility that in addition to the long-range connections between the VLPO and ascending arousal system, sleep-wake switches also depend on the local reciprocal inhibition between the sleep- and wake-active GABAergic neurons and between GABAergic and cholinergic neurons within the basal forebrain/preoptic area (Figure 2, light red and blue arrows). Furthermore, the wake-active neurons in this region may also project to the brainstem and hypothalamus, Selleck Obeticholic Acid DAPT research buy innervating the cholinergic, monoaminergic, as well as glutamatergic or GABAergic neurons (Figure 2, light red arrows). Thus, the flip-flop circuit for sleep-wake switches may involve

multiple loops of excitation and inhibition. Given the large number of GABAergic neurons in the basal forebrain/preoptic area and the importance of GABAergic transmission in sleep-wake regulation (Monti et al., 2010), delineating the functional organization of these neurons may be a key step toward understanding the subcortical circuits controlling brain states. Studies in the neocortex and hippocampus have shown that GABAergic

neurons with distinct molecular markers exhibit different physiological properties and innervation patterns (Ascoli et al., 2008; Fishell and Rudy, 2011), and they play different roles in sensory processing (Lee et al., 2012; Wilson et al., 2012). In the basal forebrain, juxtacellular recordings from a small number of immunocytochemically identified neurons suggest that cells with different sleep-wake activity patterns may also express distinct molecular markers (Duque et al., 2000). Since a large number of Cre driver mouse lines targeting different subtypes of GABAergic neurons have now become available (Taniguchi Rolziracetam et al., 2011), a promising approach is to make a targeted recording from each cell type to determine their sleep-wake activity patterns. Optogenetic manipulation of their activity in a bidirectional manner (Chow et al., 2010; Deisseroth, 2011), which has been achieved in various neuronal circuits, can further establish the causal role of these neurons in brain state regulation (Figure 4). Moreover, recent advances in viral tracing techniques (Wickersham et al., 2007) may greatly facilitate the dissection of synaptic connectivity among the various neuronal subtypes. The thalamus is the gateway of sensory inputs to the cortex, and it receives massive cortical feedback.