The addicted brain craves new neurons: putative role for adult-born progenitors in promoting recovery

Abstract

Addiction is a chronic relapsing disorder associated with compulsive drug taking, drug seeking and a loss of control in limiting intake, reflected in three stages of a recurrent cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation ("craving"). This review discusses the role of adult-born neural and glial progenitors in drug seeking associated with the different stages of the addiction cycle. A review of the current literature suggests that the loss of newly born progenitors, particularly in hippocampal and cortical regions, plays a role in determining vulnerability to relapse in rodent models of drug addiction. The normalization of drug-impaired neurogenesis or gliogenesis may help reverse neuroplasticity during abstinence and, thus, may help reduce the vulnerability to relapse and aid recovery.

Figure 1

(A) Coronal section through the adult rat brain at bregma −3.6 highlighting the hippocampal dentate gyrus (yellow with black and gray shaded regions). The hippocampal trisynaptic pathway is indicated: perforant path (PP) connections in violet, mossy fiber (mf) connections in pink, and Schaffer collaterals (Sch) connections in green. The dentate gyrus is subdivided into the molecular layer (Mol), granule cell layer (GCL, gray), and hilus (H, yellow). The subgranular zone (SGZ) is indicated as a black hatched area between the granule cell layer and the hilus of the dentate gyrus. A granule cell neuron is indicated in the GCL, which is magnified in (B) to depict the various developmental milestones of hippocampal neural stem cells. (B) Schematic of the hippocampal GCL demonstrating the sequence of preneuronal, early neuronal, and postmitotic cell types during postnatal neurogenesis. Cells are born as type-1 radial glia-like stem cells and slowly divide to produce type-2 cells. Rapidly dividing type-2 cells differentiate into immature neuron type-3 cells and finally into a mature granule cell neuron. Various endogenous markers of proliferation (Sox2, Ki-67) and differentiation (DCX, PSA-NCAM, NeuroD1) can be used in combination with the astrocytic maker GFAP to determine the cell type of proliferating cells.

Figure 2

(A) The adult rat medial prefrontal cortex (mPFC), which is equivalent to the human dorsolateral PFC, spans a 3 mm³ area bilaterally along the rostral-caudal levels of the rodent brain [18]. Anatomically, the mPFC is clearly distinguishable from other cortical areas in bregma regions 3.7-2.2 of the adult rat brain [92]. A coronal section through the adult rat brain at bregma 2.7 highlights the mPFC in tan color. The mPFC is further divided into the anterior cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) subregions [130]. LV, lateral ventricle). (B) The mPFC contains proliferating cells (black filled circles; one cell in a rectangle box is enlarged and is a cycling cell in yellow) that mostly mature into glia (oligodendrocytes in blue and astrocytes in green) and endothelial cells (blue cells in blood vessels) or neurons (red) to a lesser extent. The percentage of mature phenotypes reflect data pooled from various reports (see below) of 20-day or older BrdU-IR cells that were co-labeled with various markers for immature (NG2; Rip) or mature (PLP, proteolipid protein; O4, oligodendrocyte marker clone O4) oligodendrocytes, mature astrocytes (GFAP; S100β, S100 calcium binding protein B), endothelial cells (RECA, pan-endothelium marker), or mature neurons [neuronal nuclease (NeuN)]. (C) Twenty-day-old or older BrdU-immunoreactive cells were colabeled with various markers for immature (NG2, Rip) or mature (PLP, O4) oligodendrocytes, mature astrocytes (GFAP, S100β), endothelial cells (RECA), immature neurons (DCX), or mature neurons (NeuN). The ratio of labeled phenotypes (y-axis) from various reports [, , –92, 94] using adult rat brain tissue (x-axis) is indicated. Such findings indicate that there is a large variability between studies, although most studies found that NG2+ cells constituted the majority of BrdU labeled cells, whereas NeuN+ cells were relatively rare.