It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the last decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine, and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering our understanding of brain mechanisms and circuits that underlie drug craving in human addicts.

Antila et al. show that meningeal lymphatic vessels in mice develop postnatally. Interruption of VEGF-C/VEGFR3 signal transduction arrests their development. In adult mice, VEGFR3 deletion and VEGFR3 blockers, including a clinically available tyrosine kinase inhibitor, induce regression of meningeal lymphatic vessels.

Background: Mesencephalic astrocyte-derived neurotrophic factor is a secreted protein with an unknown mechanism of action. Results: KDEL-like sequence of MANF ("RTDL") is required for ER retention, secretory responsiveness to ER stress, and surface binding. Conclusion: KDEL receptors modulate secretion and surface binding of MANF. Significance: The plasma membrane localization of KDELRs has implications for MANF and other KDEL-containing proteins.

Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that are critical for the growth, survival, and differentiation of developing neurons. These neurotrophic factors also play important roles in the survival and function of adult neurons, learning and memory, and synaptic plasticity. Since the mid 1990s, investigators have studied the role of BDNF and GDNF in the behavioral effects of abused drugs and in the neuroadaptations induced by repeated exposure to drugs in the mesocorticolimbic dopamine system. Here, we review rodent studies on the role of BDNF and GDNF in drug reward, as assessed in the drug self-administration and the conditioned place preference procedures, and in drug relapse, as assessed in extinction and reinstatement procedures. Our main conclusion is that whether BDNF or GDNF would facilitate or inhibit drug-taking behaviors is dependent on the drug type, brain site, the addiction phase (initiation, maintenance, or abstinence/relapse), and the time interval between sitespecific BDNF or GDNF injections and the reward-and relapse-related behavioral assessments.

Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as Arginine-rich, Mutated in Early Stage of Tumors (ARMET), is a secreted protein which reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition which induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MANF after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at two days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex.

Astrocytes, oligodendrocytes, and microglia are abundant cell types found in the central nervous system and have been shown to play crucial roles in regulating both normal and disease states. An increasing amount of evidence points to the critical importance of glia in mediating neurodegeneration in Alzheimer’s and Parkinson’s diseases (AD, PD), and in ischemic stroke, where microglia are involved in initial tissue clearance, and astrocytes in the subsequent formation of a glial scar. The importance of these cells for neuronal survival has previously been studied in co-culture experiments and the search for neurotrophic factors (NTFs) initiated after finding that the addition of conditioned media from astrocyte cultures could support the survival of primary neurons in vitro . This led to the discovery of the potent dopamine neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). In this review, we focus on the relationship between glia and NTFs including neurotrophins, GDNF-family ligands, CNTF family, and CDNF/MANF-family proteins. We describe their expression in astrocytes, oligodendrocytes and their precursors (NG2-positive cells, OPCs), and microglia during development and in the adult brain. Furthermore, we review existing data on the glial phenotypes of NTF knockout mice and follow NTF expression patterns and their effects on glia in disease models such as AD, PD, stroke, and retinal degeneration.

Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to the evolutionarily conserved CDNF/MANF family of neurotrophic factors. CDNF has been shown to promote the survival of midbrain dopamine neurons in vivo. The degeneration of dopamine neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treatment is well characterized and efficacy in this model is considered a standard criterion for development of parkinsonian therapies. MPTP is a neurotoxin, which produces parkinsonian symptoms in humans, and in C57/Bl6 mice. To date, there are no reports about the effects of CDNF on dopamine neuron survival or function in the MPTP rodent model, a critical gap. Therefore, we studied whether CDNF has neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections in C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20-h before MPTP, improved horizontal and vertical motor behavior. CDNF pre-treatment increased tyrosine hydroxylase (TH)-immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Post-treatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the TH-positive cells in the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson’s disease.

Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.