Cooke Spencer K, Martin Andrea J, Spencer Robert C, Nicol Shannon E, Berridge Craig W
Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin.
Biol Psychiatry. 2025 Mar 27. doi: 10.1016/j.biopsych.2025.03.011.
Impairment of prefrontal cortex (PFC)-dependent cognition is associated with multiple psychiatric disorders. Development of more effective treatments for this form of cognitive dysfunction is hindered by our limited understanding of the neurobiology underlying PFC-dependent cognition. We previously identified a robust population of corticotropin-releasing factor (CRF) neurons in the caudal dorsomedial PFC (dmPFC) of rats that impair both working memory and sustained attention. Although the working memory actions of these neurons involved local CRF release, the sustained attention actions did not. These results suggest potential heterogeneity within this population of CRF neurons, including the potential existence of both GABAergic (gamma-aminobutyric acidergic) (CRF) interneurons and glutamatergic (CRF) CRF projection neurons.
Immunohistochemical analyses first identified both CRF and CRF neurons in the caudal dmPFC. Intersectional viral vector chemogenetic approaches were then used to assess the effects of activating caudal dmPFC CRF and CRF neurons on working memory and sustained attention in males and females (tested outside of proestrus).
CRF neurons comprised a majority (85%) of caudal dmPFC CRF neurons, while the remaining were identified as CRF neurons. For both females and males, activation of caudal dmPFC CRF neurons impaired working memory but not sustained attention, while activation of CRF neurons impaired both working memory and sustained attention. Interestingly, the working memory actions of both CRF and CRF neurons were dependent on local CRF receptors.
These results advance our understanding of the neurobiology of PFC-dependent cognition and potential mechanisms through which cognitive dysfunction could arise.
前额叶皮质（PFC）依赖的认知功能受损与多种精神疾病相关。我们对PFC依赖认知背后的神经生物学了解有限，这阻碍了针对这种认知功能障碍开发更有效的治疗方法。我们之前在大鼠尾侧背内侧PFC（dmPFC）中发现了一群强大的促肾上腺皮质激素释放因子（CRF）神经元，它们会损害工作记忆和持续注意力。虽然这些神经元的工作记忆作用涉及局部CRF释放，但持续注意力作用并非如此。这些结果表明该CRF神经元群体中可能存在异质性，包括可能存在GABA能（γ-氨基丁酸能）（CRF）中间神经元和谷氨酸能（CRF）CRF投射神经元。
免疫组织化学分析首先在尾侧dmPFC中鉴定出CRF和CRF神经元。然后使用交叉病毒载体化学遗传学方法评估激活尾侧dmPFC的CRF和CRF神经元对雄性和雌性（在动情前期之外进行测试）工作记忆和持续注意力的影响。
CRF神经元占尾侧dmPFC中CRF神经元的大多数（85%），而其余的被鉴定为CRF神经元。对于雌性和雄性，激活尾侧dmPFC的CRF神经元会损害工作记忆，但不会损害持续注意力，而激活CRF神经元会损害工作记忆和持续注意力。有趣的是，CRF和CRF神经元的工作记忆作用都依赖于局部CRF受体。
这些结果推进了我们对PFC依赖认知的神经生物学以及认知功能障碍可能出现的潜在机制的理解。
